"Instead, we got these highly synergistic grip conformations," Marasco says.
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It can use trip conformations from your e-mail to autofill the dates of the car bookings.
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Some of these conformations act like templates that recruit nearby PrP to fold in the same way, stacking into brain-scrambling spikes.
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Modeling realistic conformations is "one of the hardest parts" of macrocycle design, according to Vikram Mulligan, another lead author of the report.
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The various prion conformations give rise to a myriad of diseases with unique but overlapping clinical presentations—kuru, fatal familial insomnia, Creutzfeldt-Jakob, and others.
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"It turns out, different conformations of this material absorb different wavelengths of light, including wavelengths that are accessible on the surface of Titan," Rahm said.
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The hinge is a beautiful little piece of engineering, and — presumably — allows the device to be used painlessly in a number of configurations (conformations, really).
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To create additional reliable starting points, his team used generalized kinematic closure — the robot joint algorithm — to explore the possible conformations, or shapes, that macrocycles can adopt.
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Additionally, while previous studies of dynein have revealed the molecule's two different static conformations, our animation visually depicts one plausible way that the protein can transition between those shapes at atomic resolution, which is something that other simulations can't do.
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One of the ways that we've genetically changed dogs is that we've bred them to have all these different breed conformations, and one of the things that we've changed pretty profoundly is the shape of the skull, which causes differences in the shape of the brain case, so there's all sorts of potential interactions going on there.
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PVDF molecules contain two hydrogen and two fluorine atoms per repeat unit, so they have a choice of multiple conformations. However, rotational barriers are relatively high, the chains can be stabilized into favorable conformations other than that of lowest energy. The three known conformations of PVDF are all-trans, tg+tg−, and . The first two conformations are the most common ones and are sketched out in the figure on right.
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Structural ambiguity in protein complexes covers a wide spectrum. In a polymorphic complex, the protein adopts two or more different conformations upon binding to the same partner, and these conformations can be resolved. Clamp, flanking and random complexes are dynamic, where ambiguous conformations interchange with each other and cannot be resolved. Interactions in fuzzy complexes are usually mediated by short motifs.
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Other programs use a de novo approach that samples sterically feasible loop conformations and selects the best one. Third, determining the best model means that a scoring method must be created to compare the various conformations.
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These polar conformations are the crucial factors that lead to the ferroelectric properties.
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The N-terminal domain only shows minor structural changes between the two different conformations.
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If each of these bond angles can be in one of three stable conformations, the protein may misfold into a maximum of 3198 different conformations (including any possible folding redundancy). Therefore, if a protein were to attain its correctly folded configuration by sequentially sampling all the possible conformations, it would require a time longer than the age of the universe to arrive at its correct native conformation. This is true even if conformations are sampled at rapid (nanosecond or picosecond) rates. The "paradox" is that most small proteins fold spontaneously on a millisecond or even microsecond time scale.
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Multiple static structures experimentally determined for the same protein in different conformations are often used to emulate receptor flexibility. Alternatively rotamer libraries of amino acid side chains that surround the binding cavity may be searched to generate alternate but energetically reasonable protein conformations.
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However, he cautions that smaller rings, particularly those in T-shaped conformations, do not behave significantly differently from their saturated counterparts, and that the term should be specified for larger rings in stacked conformations which do seem to exhibit a cooperative pi electron effect.
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Different conformations of the molecule are Gauche-gauce (Gg), Gauche-gauce' (Gg'), and Trans-gauche (Tg).
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Knowledge-based functions are formed with statistical models capturing aspects of the properties of native protein conformations.
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Desmosine has pathways for form multiple conformations of itself, both through biosynthesis and through man- made systems.
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Unsubstituted metallacyclopentanes adopt conformations related to cyclopentane itself: open-envelope conformation and a twisted open-envelope structure.
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Osmolytes exert their chaperoning effects indirectly by changing the interaction of the protein with solvent, rather than through any direct interaction with the protein. Unfavorable interactions between proteins and osmolytes increases the solvation of the protein with water. This increased hydration favors more compact polypeptide conformations, in which hydrophobic residues are more tightly sequestered from polar solvent. Thus, osmolytes are thought to work by structuring partially folded intermediates and thermodynamically stabilizing folded conformations to a greater extent than unfolded conformations.
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This is a consequence of the free rotation about a carbon–carbon single bond. Despite this apparent freedom, only two limiting conformations are important: eclipsed conformation and staggered conformation. The two conformations differ in energy: the staggered conformation is 12.6 kJ/mol lower in energy (more stable) than the eclipsed conformation (the least stable). This difference in energy between the two conformations, known as the torsion energy, is low compared to the thermal energy of an ethane molecule at ambient temperature.
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Therefore, the tAqpZ structure has two different Arg-189 conformations which provide water permeation through the channel. Alternating between the two Arg-189 conformations disrupts continuous flow of water, thus regulating the open probability of the water pore. Further, the difference in Arg-189 displacements is correlated with a strong electron density found between the first transmembrane helices of two open channels, suggesting that the observed Arg-189 conformations are stabilized by asymmetrical subunit interactions in tAqpZ. Other resolved crystal structures for AqpZ include: , , .
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Entropy also plays a role in a substituent's preference for the equatorial position. The entropic component is determined by the following formula: : \Delta S = R \ln \sigma Where σ is equal to the number of microstates available for each conformation. Possible axial conformations of ethyl cyclohexane. Possible equatorial conformations of ethyl cyclohexane.
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P-ATPases may be composed of one or two polypeptides, and can usually take two main conformations, E1 and E2.
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These methods use rotamer libraries, which are collections of favorable conformations for each residue type in proteins. Rotamer libraries may contain information about the conformation, its frequency, and the standard deviations about mean dihedral angles, which can be used in sampling. Rotamer libraries are derived from structural bioinformatics or other statistical analysis of side-chain conformations in known experimental structures of proteins, such as by clustering the observed conformations for tetrahedral carbons near the staggered (60°, 180°, -60°) values. Rotamer libraries can be backbone-independent, secondary-structure- dependent, or backbone-dependent.
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225px Similar to cyclooctane, a cyclodecane ring exhibits several conformations with two lower energy conformations. The boat-chair-boat conformation is energetically minimized, while the chair-chair-chair conformation has significant eclipsing interactions. These ground-state conformational preferences are useful analogies to more highly functionalized macrocyclic ring systems, where local effects can still be governed to first approximation by energy minimized conformations even though the larger ring size allows more conformational flexibility of the entire structure. For example, in methyl cyclodecane, the ring can be expected to adopt the minimized conformation of boat-chair-boat.
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Allyic strain was first recognized in the literature in 1965 by Johnson and Malhotra. The authors were investigating cyclohexane conformations including endocyclic and exocylic double bonds when they noticed certain conformations were disfavored due to the geometry constraints caused by the double bond. Organic chemists capitalize on the rigidity resulting from allylic strain for use in asymmetric reactions.
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Residues in beta hairpins with loops of 2, 3, or 4 residues have distinct conformations. However, a wide range of conformations can be seen in longer loops, which are sometimes referred to as 'random coils'. A beta-meander consists of consecutive antiparallel-beta strands linked by hairpins. Two residue loops are called beta turns or reverse turns.
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Macrocycles can access a number of stable conformations, with preference to reside in conformations that minimize transannular nonbonded interactions within the ring (e.g., with the chair and chair-boat being more stable than the boat-boat conformation for cyclooctane, because of the interactions depicted by the arcs shown). Medium rings (8-11 atoms) are the most strained, with between 9-13 (kcal/mol) strain energy, and analysis of factors important in the conformations of larger macrocycles can be modeled using medium ring conformations.Eliel, E.L., Wilen, S.H. and Mander, L.S. (1994) Stereochemistry of Organic Compounds, John Wiley and Sons, Inc.
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Conformations of the ligand may be generated in the absence of the receptor and subsequently docked or conformations may be generated on-the-fly in the presence of the receptor binding cavity, or with full rotational flexibility of every dihedral angle using fragment based docking. Force field energy evaluation are most often used to select energetically reasonable conformations, but knowledge-based methods have also been used. Peptides are both highly flexible and relatively large-sized molecules, which makes modeling their flexibility a challenging task. A number of methods were developed to allow for efficient modeling of flexibility of peptides during protein-peptide docking.
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For proteins in which subunits exist in more than two conformations, the allostery landscape model described by Cuendet, Weinstein, and LeVine, can be used.
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Conformations of ferrocene. Left: staggered; right: ecliptic. An important parameter is the angle between the two cyclopentadienyl ligands. Often the reactivity increases with increasing angle.
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In physical knot theory, a knot energy is a functional on the space of all knot conformations. A conformation of a knot is a particular embedding of a circle into three-dimensional space. Depending on the needs of the energy function, the space of conformations is restricted to a sufficiently nicely behaved class. For example, one may consider only polygonal circles or C2 functions.
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The detailed mechanism of the chair-to-chair interconversion has been the subject of much study and debate. The half-chair state (D, in figure below) is the key transition state in the interconversion between the chair and twist-boat conformations. The half-chair has D2 symmetry. The interconversion between the two chair conformations involves the following sequence: chair → half-chair → twist-boat → half-chair′ → chair′.
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The anti conformation of butane is approximately 0.9 kcal mol−1 (3.8 kJ mol−1) more stable than the gauche conformation. Both of these staggered conformations are much more stable than the eclipsed conformations. Instead of a hyperconjugative effect, such as that in ethane, the strain energy in butane is due to both steric interactions between methyl groups and angle strain caused by these interactions.
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The peripheral attack model is based on predicting lowest energy conformations of an inherently complicated system, where nuanced perturbations can cause huge stereodifferentiating consequences. By modeling peripheral attack using the Curtin-Hammett scenario depicted above, the transition state is excluded from this conformation analysis by assuming that the barrier to each transition state from a given conformation is the same and thus that ground state conformations are the sole product determining factor. A significant criticism is the mapping of medium-sized ring conformations and influences onto larger ring systems. Macrocycles can possess varying degrees of rigidity in their structure, making a single peripheral attack model difficult to apply to all systems.
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The secondary bonds of a polymer constantly break and reform due to thermal motion. Application of a stress favors some conformations over others, so the molecules of the polymer will gradually "flow" into the favored conformations over time.S.A. Baeurle, A. Hotta, A.A. Gusev, Polymer 47, 6243-6253 (2006). Because thermal motion is one factor contributing to the deformation of polymers, viscoelastic properties change with increasing or decreasing temperature.
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The structure of the crystallized form was determined by J. D. Oliver and L. C. Strickland in 1984, using X-ray diffraction. The crystal system is orthorombic, symmetry group P212121, with parameters a = 1.835 nm, b= 2.144 nm, c= 0.835 nm, Z=4, V=3.285 nm3, Dx = 1.372 g/mL. The pyranose and furanose rings are in "chair" (4C1) and "twist" (4T1) conformations, respectively, unlike their conformations in saccharose.
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2, an isoprene unit has three single C-C bonds and there are two or three preferred rotational angles (orientations) about these bonds that have energy minima. Of the18 allowed rotational conformations, only 6 have extended end-to-end distances and forcing the isoprene units in a chain to reside in some subset of the extended states must reduce the number of rotational conformations available for thermal motion. It is this reduction in the number of available states that causes the entropy to decrease. As the chain continues to straighten, all of the isoprene units in the chain are eventually forced into extended conformations and the chain is considered to be ‘taut’.
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The number of candidate protein sequences, however, grows exponentially with the number of protein residues; for example, there are 20100 protein sequences of length 100. Furthermore, even if amino acid side-chain conformations are limited to a few rotamers (see Structural flexibility), this results in an exponential number of conformations for each sequence. Thus, in our 100 residue protein, and assuming that each amino acid has exactly 10 rotamers, a search algorithm that searches this space will have to search over 200100 protein conformations. The most common energy functions can be decomposed into pairwise terms between rotamers and amino acid types, which casts the problem as a combinatorial one, and powerful optimization algorithms can be used to solve it.
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The boat conformation (C, below) is a transition state, allowing the interconversion between two different twist-boat conformations. While the boat conformation is not necessary for interconversion between the two chair conformations of cyclohexane, it is often included in the reaction coordinate diagram used to describe this interconversion because its energy is considerably lower than that of the half-chair, so any molecule with enough energy to go from twist-boat to chair also has enough energy to go from twist- boat to boat. Thus, there are multiple pathways by which a molecule of cyclohexane in the twist-boat conformation can achieve the chair conformation again. :Conformations: chair (A), twist-boat (B), boat (C) and half-chair (D).
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The model that describes the conformational changes associated with the binding of the substrate is the alternating-access model. In this model, the substrate binding site alternates between outward- and inward- facing conformations. The relative binding affinities of the two conformations for the substrate largely determines the net direction of transport. For importers, since translocation is directed from the periplasm to the cytoplasm, the outward-facing conformation has higher binding affinity for the substrate.
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While structures are available for many of the subunits and their interfaces, a structure of the entire cohesin complex has not been solved. Our knowledge of the conformation of cohesin comes largely from electron microscopy. These studies have revealed cohesin in numerous conformations including rings, elongated rods and most recently in a folded conformations. It is not known which conformation is predominant inside the cell and whether some are induced by sample preparation.
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Differently linked chains have specific effects on the protein to which they are attached, caused by differences in the conformations of the protein chains. K29-, K33-, K63- and M1-linked chains have a fairly linear conformation; they are known as open-conformation chains. K6-, K11-, and K48-linked chains form closed conformations. The ubiquitin molecules in open-conformation chains do not interact with each other, except for the covalent isopeptide bonds linking them together.
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The position of these arginines, known as gating arginines, are highly conserved in all voltage- gated potassium, sodium, or calcium channels. However, the extent of their movement and their displacement across the transmembrane potential has been subject to extensive debate. Specific domains of the channel subunits have been identified that are responsible for voltage-sensing and converting between the open and closed conformations of the channel. There are at least two closed conformations.
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All relative conformational energies are shown below. The molecule can easily switch between these conformations, and only two of them—chair and twist-boat—can be isolated in pure form.
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Right of 1st of June there isn't any plans for a Broadway run, nor there is any conformations that the creators of the show are planning to go to Broadway.
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Pulses of UV illumination would thus provide pulses of movement. DNA nanomachines, based on changes between two molecular conformations of DNA in response to various external triggers, have also been described.
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F1P and F6P both bind to the same site on GKRP. It is postulated that they produce 2 different conformations of GKRP, one able to bind GK and the other not.
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The optical resolution is a standard component of inorganic synthesis courses.Girolami, G. S.; Rauchfuss, T. B. and Angelici, R. J., Synthesis and Technique in Inorganic Chemistry, University Science Books: Mill Valley, CA, 1999 Because of its nonplanarity, the MN2C2 rings can adopt either of two conformations, which are described by the symbols λ and δ. The registry between these ring conformations and the absolute configuration of the metal centers is described by the nomenclature lel (when the en backbone lies parallel with the C3 symmetry axis) or ob (when the en backbone is obverse to this same C3 axis). Thus, the following diastereomeric conformations can be identified: Δ-(lel)3, Δ-(lel)2(ob), Δ-(lel)(ob)2, and Δ-(ob)3.
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The critical mutation in cyan derivatives is the Y66W substitution, which causes the chromophore to form with an indole rather than phenol component. Several additional compensatory mutations in the surrounding barrel are required to restore brightness to this modified chromophore due to the increased bulk of the indole group. In ECFP and Cerulean, the N-terminal half of the seventh strand exhibits two conformations. These conformations both have a complex set of van der Waals interactions with the chromophore.
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Lysozyme exhibits two conformations: an open active state and a closed inactive state. The catalytic relevance was examined with single walled carbon nanotubes (SWCN) field effect transistors (FETs), where a singular lysozyme was bound to the SWCN FET. Electronically monitoring the lysozyme showed two conformations, an open active site and a closed inactive site. In its active state lysozyme is able to processively hydrolyze its substrate, breaking on average 100 bonds at a rate of 15 per second.
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Action potentials result from the presence in a cell's membrane of special types of voltage-gated ion channels. A voltage-gated ion channel is a cluster of proteins embedded in the membrane that has three key properties: #It is capable of assuming more than one conformation. #At least one of the conformations creates a channel through the membrane that is permeable to specific types of ions. #The transition between conformations is influenced by the membrane potential.
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Early investigations of macrocyclic stereocontrol studied the alkylation of 8-membered cyclic ketones with varying substitution. In the example below, alkylation of 2-methylcyclooctanone occurred to yield the predominantly trans product. Proceeding from the lowest energy conformation of 2-methylcycloctanone, peripheral attack is observed from either one of the low energy (energetic difference of 0.5 (kcal/mol)) enolate conformations, resulting in a trans product from either of the two depicted transition state conformations."Classics in Stereoselective Synthesis".
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To deal with this problem, one can make use of decoys. The idea behind this is that it is unnecessary to search blindly through all possible conformations for the native conformation; the search can be limited to a relevant sub-set of structures. To start with, all non-compact configurations can be excluded. A typical decoy set will include globular conformations of various shapes, some having no secondary structures, some having helices and sheets in different proportions.
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When comparing relative stability, 6- and 7-atom interactions can be used to approximate differences in enthalpy between conformations. Each 6-atom interaction is worth and each 7-atom interaction is worth .
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This is not to say that nearly identical amino acid sequences always fold similarly. Conformations differ based on environmental factors as well; similar proteins fold differently based on where they are found.
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Hypothetic models of VAMP2 conformations and engagement in SNARE complex assembly for neurotransmitter release Vesicle-associated membrane protein 2 (VAMP2) is a protein that in humans is encoded by the VAMP2 gene.
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It could mean that there is a hitherto uncharacterized kinetic isotope effect associated with the incorporation of sulfate into a particular carbonate texture (shrubs vs. nodules vs. acicular cements vs. other conformations).
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Equivalently the bridge number is the minimal number of local maxima of the projection of the knot onto a vector, where we minimize over all projections and over all conformations of the knot.
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In many subtle cases, such as the one below, decreased nonbonding interactions in dominant conformations of the favored isomers are often invokedBrunner, H.; Stöhr, F. Eur. J. Org. Chem. 2000, 2777. (5)File:KetolScopeA.
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Accurate packing of the amino acid side chains represents a separate problem in protein structure prediction. Methods that specifically address the problem of predicting side-chain geometry include dead-end elimination and the self-consistent mean field methods. The side chain conformations with low energy are usually determined on the rigid polypeptide backbone and using a set of discrete side chain conformations known as "rotamers." The methods attempt to identify the set of rotamers that minimize the model's overall energy.
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The accuracy of such short loops may be almost as accurate as that of the homology model upon which it is based. It should also be considered that the loops in proteins may not be well-structured and therefore have no one conformation that could be predicted; NMR experiments indicate that solvent-exposed loops are "floppy" and adopt many conformations, while the loop conformations seen by X-ray crystallography may merely reflect crystal packing interactions, or the stabilizing influence of crystallization co-solvents.
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Amyloids may also have normal biological functions; for example, in the formation of fimbriae in some genera of bacteria, transmission of epigenetic traits in fungi, as well as pigment deposition and hormone release in humans. Amyloids have been known to arise from many different proteins. These polypeptide chains generally form β-sheet structures that aggregate into long fibers; however, identical polypeptides can fold into multiple distinct amyloid conformations. The diversity of the conformations may have led to different forms of the prion diseases.
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Macrocycles can access a number of stable conformations, with preferences to reside in those that minimize the number of transannular nonbonded interactions within the ring. Medium rings (8-11 atoms) are the most strained with between 9-13 (kcal/mol) strain energy; analysis of the factors important in considering larger macrocyclic conformations can thus be modeled by looking at medium ring conformations.Eliel, E.L., Wilen, S.H. and Mander, L.S. (1994) Stereochemistry of Organic Compounds, John Wiley and Sons, Inc., New York.
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In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the molecule has an astronomical number of possible conformations. An estimate of 3300 or 10143 was made in one of his papers. Levinthal's paradox is a thought experiment based on the observation that if a protein were folded by sequentially sampling of all possible conformations, it would take an astronomical amount of time to do so, even if the conformations were sampled at a rapid rate (on the nanosecond or picosecond scale). Based upon the observation that proteins fold much faster than this, Levinthal then proposed that a random conformational search does not occur, and the protein must, therefore, fold through a series of meta-stable intermediate states.
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The different conformations ensure that only preferential binding occurs in the active site. In the presence of a slow substrate, Gly794 activity increased as well as an increase in galactosylation and decrease in degalactosylation.
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Figure 2. Three conformations of FAN1 in action. A. Monomer scans substrate B. Dimerization occurs and dimer latches onto substrate C. dimer unwinds substrate. Created in PyMOL from PDB structures 4REA, 4REC, and 4REB.
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Generally, phosphorylation causes interdomain locking, which changes Rb's conformation and prevents binding to target proteins. Different sites may be phosphorylated at different times, giving rise to many possible conformations and likely many functions/activity levels.
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Three distinct conformational states of the 26S proteasome. The conformations are hypothesized to be responsible for recruitment of the substrate, its irreversible commitment, and finally processing and translocation into the core particle, where degradation occurs.
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If the bonds are rotated in the same direction, this doesn't occur. The steric strain between the two terminal methyl groups accounts for the difference in energy between the two similar, yet very different conformations.
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Domain II and III are unstructured, shown by NMR studies. Domain I is preceded by an N-terminal amphipathic helix which allows the protein to associate with endoplasmic reticulum-derived membranes. Although X-ray crystallographic studies revealed dimer conformations of NS5A domain1, recent in solution structural characterization studies showed that NS5A proteins form higher-order structures by dimeric subunits of NS5A domain 1. Moreover, the overall structural model of NS5A highlights the variability of intrinsic conformations of the D2 and D3 domains between HCV genotypes.
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Protein folding does not occur in one step. Instead, proteins spend most of their folding time, nearly 96% in some cases, waiting in various intermediate conformational states, each a local thermodynamic free energy minimum in the protein's energy landscape. Through a process known as adaptive sampling, these conformations are used by Folding@home as starting points for a set of simulation trajectories. As the simulations discover more conformations, the trajectories are restarted from them, and a Markov state model (MSM) is gradually created from this cyclic process.
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A protein folded into its native state or native conformation typically has a lower Gibbs free energy (a combination of enthalpy and entropy) than the unfolded conformation. A protein will tend towards low-energy conformations, which will determine the protein's fold in the cellular environment. Because many similar conformations will have similar energies, protein structures are dynamic, fluctuating between a large these similar structures. Globular proteins have a core of hydrophobic amino acid residues and a surface region of water-exposed, charged, hydrophilic residues.
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Evans, D. A.; Ripin, D.H.B.; Halstead, D.P.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 6816-6826. Computational modeling can predict conformations of medium rings with reasonable accuracy, as Still used molecular mechanics modeling computations to predict ring conformations to determine potential reactivity and stereochemical outcomes. Reaction classes used in synthesis of natural products under the macrocyclic stereocontrol model for obtaining a desired stereochemistry include: hydrogenations such as in neopeltolide Tu, W.; Floreancig, P. E. Angew. Chem. Int. Ed. 2009, 48, 4567-4571.
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While any two arrangements of atoms in a molecule that differ by rotation about single bonds can be referred to as different conformations, conformations that correspond to local minima on the energy surface are specifically called conformational isomers or conformers. Conformations that correspond to local maxima on the energy surface are the transition states between the local-minimum conformational isomers. Rotations about single bonds involve overcoming a rotational energy barrier to interconvert one conformer to another. If the energy barrier is low, there is free rotation and a sample of the compound exists as a rapidly equilibrating mixture of multiple conformers; if the energy barrier is high enough then there is restricted rotation, a molecule may exist for a relatively long time period as a stable rotational isomer or rotamer (an isomer arising from hindered single-bond rotation).
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Although doing so is quite difficult, one can, by observing the energy distribution of a large number of conformations, despite the almost infinite number of different protein conformations possible for any given protein (see Levinthal Paradox), with a reasonably large number of protein energy samplings, predict relatively closely what conformation, within a range of conformations, has the expected lowest energy using methods in statistical inference. There are other factors such as salt concentration, pH, ambient temperature or chaperonins, which are proteins that assist in the folding process of other proteins, that can greatly affect how a protein folds. However, if the given protein is shown to fold on its own, especially in vitro, these findings can be further supported. Once we can see how a protein folds then we can see how it works as a catalyst, or in intracellular communication, e.g.
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J. Chem. Theory. Comput., 2013, 9 (9), Possible fluorographene conformations have been extensively investigated computationally.Artyukhov, V. I. and Chernozatonskii, L. A., Structure and Layer Interaction in Carbon Monofluoride and Graphane: A Comparative Computational Study. J. Phys. Chem.
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A protein generally undergoes reversible structural changes in performing its biological function. The alternative structures of the same protein are referred to as different conformational isomers, or simply, conformations, and transitions between them are called conformational changes.
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The energy of the asymmetric 1,3,7-trihydro-2,5,8-trioxo form is estimated to be 5.61 kcal/mol higher, and that of the two conformations of the trihydroxy form are 19.84 (symmetric) and 20.18 (asymmetric) kcal/mol higher.
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This led to the conclusion that the transfer of a glucose to the Man9GlcNAc2 was the only way that Glc1Man9GlcNAc2 could have been made. Parodi also looked into how glucosylation/deglucosylation in the ER’s lumen were involved with the correct folding of N-linked glycoproteins. His research led him to find that misfolding allowed for conformations that would allow for glycoproteins to act as glucose acceptors. He was able to find this using UDP-Glc: glycoprotein GT that worked as ways of sensing the various conformations of the glycoproteins.
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Isocitrate dehydrogenase is a digestive enzyme that is used in the citric acid cycle. Its main function is to catalyze the oxidative decarboxylation of isocitrate into alpha-ketoglutarate. Human isocitrate dehydrogenase regulation is not fully understood however, it is known that NADP and Ca2+ bind in the active site to create three different conformations. These conformations form in the active site and are as follows: a loop is form in the inactive enzyme, a partially unraveled alpha helix in the semi open form, and an alpha helix in the active form.
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Ligands with a C2 symmetry element have been particularly popular, in part because the presence of such an element reduces the possible binding conformations of a substrate to a metal-ligand complex dramatically (often resulting in exceptional enantioselectivity).
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The protein consists of 4 subunits: α, β, γ, and δ subunits. There are two α subunits, with one acetylcholine binding site each. This receptor can exist in three conformations. The closed and unoccupied state is the native protein conformation.
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The actual structure will always differ somewhat from these idealized forms, as the differences in energy between the conformations are small compared to the thermal energy of the molecules: Alkane molecules have no fixed structural form, whatever the models may suggest.
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These different conformations create more variety in the structure. There are examples of coordination polymers that include two configurations of the same ligand within one structure, as well as two separate structures where the only difference between them is ligand orientation.
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Since constitutively active B-Raf mutants commonly cause cancer (see Clinical Significance) by excessively signaling cells to grow, inhibitors of B-Raf have been developed for both the inactive and active conformations of the kinase domain as cancer therapeutic candidates.
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These interactions, called transannular interactions, arise from a lack of space in the interior of the ring, which forces substituents into conflict with one another. In medium-sized cycloalkanes, which have between 8 and 11 carbons constituting the ring, transannular strain can be a major source of the overall strain, especially in some conformations, to which there is also contribution from large-angle strain and Pitzer strain.Smith and March, March's Advanced Organic Chemistry, John Wiley & Sons Inc., 2007, In larger rings, transannular strain drops off until the ring is sufficiently large that it can adopt conformations devoid of any negative interactions.
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Unlike dead-end elimination, SCMF is not guaranteed to converge on the optimal solution. However, it is deterministic (as in, it will converge to the same solution every time given the same initial conditions), unlike alternatives that rely on Monte Carlo analysis. By comparison to DEE, which is guaranteed to find the optimal solution, SCMF is faster but less accurate overall; it is significantly better at identifying correct side chain conformations in the protein's core than it is on identifying correct surface conformations. Geometric packing constraints are less restrictive on the surface and thus provide fewer boundaries to the conformational search.
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The link between protein chemical shifts and protein secondary structure (specifically alpha helices) was first described by John Markley and colleagues in 1967. With the development of modern 2-dimensional NMR techniques, it became possible to measure more protein chemical shifts. With more peptides and proteins were being assigned in the early 1980s it soon became obvious that amino acid chemical shifts were sensitive not only to helical conformations, but also to β-strand conformations. Specifically, the secondary 1Hα chemical shifts of all amino acids exhibit a clear upfield trend on helix formation and an obvious downfield trend on β-sheet formation.
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In that case, the two isomers may as well be considered a single isomer, depending on the temperature and the context. For example, the two conformations of cyclohexane convert to each other quite rapidly at room temperature (in the liquid state), so that they are usually treated as a single isomer in chemistry. In some cases, the barrier can be crossed by quantum tunneling of the atoms themselves. This last phenomenon prevents the separation of stereoisomers of fluorochloroamine or hydrogen peroxide , because the two conformations with minimum energy interconvert in a few picoseconds even at very low temperatures.
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An α-glycosidic bond is formed when both carbons have the same stereochemistry, whereas a β-glycosidic bond occurs when the two carbons have different stereochemistry. One complicating issue is that the alpha and beta conformations were originally defined based on the relative orientation of the major constituents in a Haworth projection. In this case, for D-sugars, a beta conformation would see the major constituent at each carbon drawn above the plane of the ring (nominally the same conformation), while alpha would see the anomeric constituent below the ring (nominally opposite conformations). For L-sugars, the definitions would then, necessarily, reverse.
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In contrast, the substrate binding affinity in exporters is greater in the inward-facing conformation. A model that describes the conformational changes in the nucleotide-binding domain (NBD) as a result of ATP binding and hydrolysis is the ATP-switch model. This model presents two principal conformations of the NBDs: formation of a closed dimer upon binding two ATP molecules and dissociation to an open dimer facilitated by ATP hydrolysis and release of inorganic phosphate (Pi) and adenosine diphosphate (ADP). Switching between the open and closed dimer conformations induces conformational changes in the TMD resulting in substrate translocation.
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The process for developing a pharmacophore model generally involves the following steps: # Select a training set of ligands – Choose a structurally diverse set of molecules that will be used for developing the pharmacophore model. As a pharmacophore model should be able to discriminate between molecules with and without bioactivity, the set of molecules should include both active and inactive compounds. # Conformational analysis – Generate a set of low energy conformations that is likely to contain the bioactive conformation for each of the selected molecules. #Molecular superimposition – Superimpose ("fit") all combinations of the low-energy conformations of the molecules.
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In E. coli, chemotaxis receptors of four different kinds interact in groups of three, and each individual receptor can exist in at least two possible conformations and has up to eight methylation sites, resulting in billions of potential states. The protein kinase CaMKII is a dodecamer of twelve catalytic subunits, arranged in two hexameric rings. Each subunit can exist in at least two distinct conformations, and each subunit features various phosphorylation and ligand binding sites. A recent model incorporated conformational states, two phosphorylation sites and two modes of binding calcium/calmodulin, for a total of around one billion possible states per hexameric ring.
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Conformational entropy is the entropy associated with the number of conformations of a molecule. The concept is most commonly applied to biological macromolecules such as proteins and RNA, but also be used for polysaccharides and other molecules. To calculate the conformational entropy, the possible conformations of the molecule may first be discretized into a finite number of states, usually characterized by unique combinations of certain structural parameters, each of which has been assigned an energy. In proteins, backbone dihedral angles and side chain rotamers are commonly used as parameters, and in RNA the base pairing pattern may be used.
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The difference is again explained in terms of bent bonds. Bent bonds also come into play in the gauche effect, explaining the preference for gauche conformations in certain substituted alkanes and the alkene cis effect associated with some unusually stable alkene cis isomers.
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This precursor fluid has been observed using environmental scanning electron microscopy (ESEM) in surfaces with pores formed in the bulk. With the introduction of the precursor film concept, the triple line can follow energetically feasible conformations, thereby correctly explaining the Cassie–Baxter model.
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Specifically, the reference scaffold structure is N–HRS1–L1–HRS2–L2–HRS3–C. HRS = IEEIQKQIAAIQKQIAAIQKQIYRM; L = TGGSGGGSGGGSGGGSGMS The linker length is long enough to allow helices to fold in parallel or anti-parallel conformations, but experiments suggest only anti-parallel folding occurs.
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Beta hairpins were originally categorized solely by the number of amino acid residues in their loop sequences, such that they were named one-residue, two-residue, etc.Sibanda, B.L.; Blundell, T.L.; Thorton, J.M. (1985). "Conformations of Beta-Hairpins in Protein Structures". Nature(London) 316 170–174.
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Dynamic surfaces have been reported that undergo changes in surface energy upon the application of an appropriate stimuli. For example, a surface presenting photon-driven molecular motors was shown to undergo changes in water contact angle when switched between bistable conformations of differing surface energies.
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Another pseudoknot occurs at the Influenza A Segment 7 Splice Site, which is used to produce the important viral M2 ion channel protein. Both pseudoknots have the possibility of alternating between hairpin loop and pseudoknot conformations, which place splicing regulatory motifs in different structural contexts.
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The conformer of methylcyclohexane with equatorial methyl is favored by relative to the conformer where methyl is axial. In cyclohexane, the two chair conformations have the same energy. The situation is more complex is substituted derivatives. In methylcyclohexane the two chair conformers are not isoenergetic.
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Unlike other S53 peptidases, it has steric constraints on the P4 substrate pocket, which might contribute to its preferential cleavage of tripeptides from the unsubstituted N-terminus of proteins. Two alternative conformations of the catalytic Asp276 are associated with the activation status of TPP1.
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The 19S regulatory particle within the 26S proteasome holoenzyme has been observed in six strongly differing conformational states in the absence of substrates to date. A hallmark of the AAA-ATPase configuration in this predominant low-energy state is a staircase- or lockwasher-like arrangement of the AAA-domains. In the presence of ATP but absence of substrate three alternative, less abundant conformations of the 19S are adopted primarily differing in the positioning of the lid with respect to the AAA-ATPase module. In the presence of ATP-γS or a substrate, considerably more conformations have been observed displaying dramatic structural changes of the AAA-ATPase module.
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Structurally, this molecule has two distinct conformations, one being a positively charged iminium form, and the other being an uncharged form, a pseudo-base. It is also found in the plants Zanthoxylum clava-herculis and Zanthoxylum rhoifolium, exhibiting antibacterial activity against Staphylococcus aureus and other human pathogens.
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A high-affinity ligand has to be known for the protein of interest and the buffer must not interfere with the binding of the radioligand. Other thermal shift assays can also select for specific conformations if a ligand of the appropriate type is added to the experiment.
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Due to the larger number of possible conformations of ethyl cyclohexane, the A value is reduced from what would be predicted based purely on enthalpic terms. Due to these favorable entropic conditions, the steric relevance of an ethyl group is similar to that of a methyl substituent.
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Each peptide in this group is derived from the same species, Conus parius. Con-Pr3 () has three different post- translational modifications. Con-Pr1 () and –Pr2 () adopt α-helical conformations in the presence of Mg2+ and Ca2+, but otherwise are generally unstructured. Conantokin-Pr3 always adopts an α-helical conformation.
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Calculated rotational energies for different conformations of 3-methyl-1-butene. Allylic 1,3-strain is most prevalent in 1c, making this conformation the highest in energy. The simplest type of molecules which exhibit allylic strain are olefins. Depending on the substituents, olefins maintain varying degrees of allylic strain.
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When a deformation is imposed on a muscle, changes in cellular and molecular conformations link the mechanical forces with biochemical signals, and the close integration of mechanical signals with electrical, metabolic, and hormonal signaling may disguise the aspect of the response that is specific to the mechanical forces.
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The four steroid rings form a rigid framework for positioning these hydrogen groups in three-dimensional space. Analogues 5 and 6 (Figure 10) are weak modulators of GABAA receptor function because the flexible side chains in these analogues do not have the conformations required for high biological activity.
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Molecular models of cyclohexane in boat and chair conformations. The carbon atoms are colored amber or blue according to whether they lie above or below the mean plane of the ring. The C–C bonds on the ring are light green. A classic example of conformational isomerism is cyclohexane.
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Rather, they must be measured through extensive tests using human subjects in laboratory settings. Optical isomers can have different detection thresholds because their conformations may cause them to be less perceivable for the human nose. It is only in recent years that such compounds were separated on gas chromatographs.
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We would expect that butane is roughly 82% anti and 18% gauche at room temperature. However, there are two possible gauche conformations and only one anti conformation. Therefore, entropy makes a contribution of 0.4 kcal in favor of the gauche conformation.Coxon and Norman, Principles of Organic Synthesis, 3rd ed.
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The add adenine riboswitch has shown three distinct stable conformations in the presence of adenine. When unbound to adenine, the mRNA sequence converts between two different non-translatable conformations, one of which is able to accept adenine into the binding pocket and conform to the adenine-bound mRNA shape. This three-stage mechanism is quite distinct from the standard two-stage explanation of riboswitch action, which assumes a single ligand-bound state and a single ligand-unbound state. This mechanistic uniqueness of the add adenine riboswitch may serve as a benefit for organisms like Vibrio vulnificus, whose varied habitats require a particularly nuanced metabolic sensitivity to a wide variety of environmental conditions.
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The ion channel hypothesis was first proposed by Arispe and colleagues in 1993 upon discovery that Aβ could form unregulated cation-selective ion channels when incorporated into planar lipid bilayers. Further research showed that a particular fragment of Aβ, Aβ (25-35), spontaneously inserts into planar lipid bilayers to form weakly selective ion channels and that membrane insertion occurs non-specifically, irreversibly, and with a broad range of oligomer conformations. Though more recent studies have found that Aβ channels can be blocked by small molecules, the broad variety of Aβ ion channel conformations and chemistries make it difficult to design a channel blocker specific to Aβ without compromising other ion channels in the cell membrane.
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Structures obtained in closed and open conformations are reversibly interconvertible by changes in the pH. A hydrogen-bonded perturbed pair of conserved aspartyl residues explains the pH dependence of this transition, and the pH regulates calcium influx in proteoliposomes. Homology models for human BI-1 provided insight into its cytoprotective activity.
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A path of this walk of N steps in three dimensions represents a conformation of a polymer with excluded volume interaction. Because of the self-avoiding nature of this model, the number of possible conformations is significantly reduced. The radius of gyration is generally larger than that of the ideal chain.
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They flash out in such bursts and capture their prey. These fast starts terminate when the pike has reached terminal velocity. During such motions, pike make "S" conformations while swimming at high rates. To decelerate, they, simply make a "C" conformation, exponentially slowing down their speed so that they can "stop".
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Peptide plane can flip in two opposite directions: implication in amyloid formation of transthyretin. J Phys Chem B 110(12):5829-33. and implicated as occurring naturally in certain protein families by examination of their dihedral angle conformations in crystal structures.Milner-White EJ, Watson JD, Qi G, Hayward S. (2006).
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The interconversion of chair conformers is called ring flipping or chair-flipping. Carbon-hydrogen bonds that are axial in one configuration become equatorial in the other, and vice versa. At room temperature the two chair conformations rapidly equilibrate. The proton NMR spectrum of cyclohexane is a singlet at room temperature.
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Figure 5: Scheme of regiospecific polymer synthesis Figure 6: Schematic description of two most common conformations of PVDF, the left one is tg+tg− and the right one is all trans, the yellow sphere represents fluorine atom, the white sphere represents hydrogen atom and the grey sphere represents the carbon atom.
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Theoretical analyisis implies a total of 16 conformational and configurational isomers, all chiral, forming 8 enantiomer pairs. Its most stable cis stereoisomer can adopt various conformations, the most stable one being shaped like a ribbon; The most stable trans-conformer is shaped like the 8-carbon equivalent chair conformation of cyclohexane.
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On a microscopic scale, relaxed rubber is a disorganized cluster of erratically changing wrinkled chains. In stretched rubber, the chains are almost linear. The restoring force is due to the preponderance of wrinkled conformations over more linear ones. For the quantitative treatment see ideal chain, for more examples see entropic force.
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Within each cycle, ATP7A interconverts between at least two different conformations, E1 and E2. In the E1 state, Cu(I) is tightly bound to the binding sites on the cytoplasmic side; in the E2 state, the affinity of ATP7A for Cu(I) decreases and Cu(I) is released on the extracellular side.
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IDPs can be validated in several contexts. Most approaches for experimental validation of IDPs are restricted to extracted or purified proteins while some new experimental strategies aim to explore in vivo conformations and structural variations of IDPs inside intact living cells and systematic comparisons between their dynamics in vivo and in vitro.
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Rotation around the C-5/C-6 bond is described by the angle ω. Three possible staggered conformations are possible:: gauche–trans (gt), gauche–gauche (gg), and trans–gauche (tg). The name indicates the interaction between O-5 and OH-6 first followed by the interaction between OH-6 and C-4.
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Alpha-, beta-, and gammaherpesviruses display a heterodimer composed of glycoprotein H (gH) and glycoprotein L (gL) on their envelopes. This receptor is involved in the cell-to-cell transmission of the virus. Glycoprotein H has two conformations. Glycoprotein L is a chaperone protein which assures that gH takes on the correct conformation.
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1,2-Bis(4-pyridyl)ethane is a flexible ligand, which can exist in either gauche or anti conformations. Ligands can be flexible or rigid. A rigid ligand is one that has no freedom to rotate around bonds or reorient within a structure. Flexible ligands can bend, rotate around bonds, and reorient themselves.
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The interconversion of helical and extended conformations at the site of a domain boundary is not uncommon. In calmodulin, torsion angles change for five residues in the middle of a domain linking α-helix. The helix is split into two, almost perpendicular, smaller helices separated by four residues of an extended strand.
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Similar (bioisosteric) functional groups common to all molecules in the set might be fitted (e.g., phenyl rings or carboxylic acid groups). The set of conformations (one conformation from each active molecule) that results in the best fit is presumed to be the active conformation. #Abstraction – Transform the superimposed molecules into an abstract representation.
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Ammonium sulfate, as well as other neutral salts, will stabilize proteins by preferential solvation. Proteins are usually stored in ammonium sulfate because it inhibits bacterial growth. With the addition of ammonium sulfate, proteins unfolded by denaturants can be pushed into their native conformations. This can be seen with the folding of recombinant proteins.
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Backbone-independent rotamer libraries make no reference to backbone conformation, and are calculated from all available side chains of a certain type (for instance, the first example of a rotamer library, done by Ponder and Richards at Yale in 1987). Secondary-structure- dependent libraries present different dihedral angles and/or rotamer frequencies for \alpha-helix, \beta-sheet, or coil secondary structures. Backbone-dependent rotamer libraries present conformations and/or frequencies dependent on the local backbone conformation as defined by the backbone dihedral angles \phi and \psi, regardless of secondary structure. The modern versions of these libraries as used in most software are presented as multidimensional distributions of probability or frequency, where the peaks correspond to the dihedral-angle conformations considered as individual rotamers in the lists.
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The precise structure of the ligands on the surface of colloidal gold NPs impact the properties of the colloidal gold particles. Binding conformations and surface packing of the capping ligands at the surface of the colloidal gold NPs tend to differ greatly from bulk surface model adsorption, largely due to the high curvature observed at the nanoparticle surfaces. Thiolate-gold interfaces at the nanoscale have been well-studied and the thiolate ligands are observed to pull Au atoms off of the surface of the particles to for “staple” motifs that have significant Thiyl-Au(0) character. The citrate-gold surface, on the other hand, is relatively less-studied due to the vast number of binding conformations of the citrate to the curved gold surfaces.
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Single-strand conformation polymorphism (SSCP), or single-strand chain polymorphism, is defined as a conformational difference of single-stranded nucleotide sequences of identical length as induced by differences in the sequences under certain experimental conditions. This property allows sequences to be distinguished by means of gel electrophoresis, which separates fragments according to their different conformations.
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However, low temperatures can also be problematic to supramolecular processes. Supramolecular chemistry can require molecules to distort into thermodynamically disfavored conformations (e.g. during the "slipping" synthesis of rotaxanes), and may include some covalent chemistry that goes along with the supramolecular. In addition, the dynamic nature of supramolecular chemistry is utilized in many systems (e.g.
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6), from Microbacterium liquefaciens. This structure (and related structures) are available through RCSB (, , , , , ). Mhp1 contains 12 transmembrane helices, 10 of which are arranged in two inverted repeats of five helices. The structures of the outward-facing open and substrate-bound occluded conformations were solved, showing how the outward-facing cavity closes upon binding of substrate.
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Thus, the primary structure is better analyzed in traditional branches of bioinformatics. However, the sequence implies restrictions that allow the formation of conserved local conformations of the polypeptide chain, such as alpha-helix, beta-sheets, and loops (secondary structure). Also, weak interactions (as hydrogen bonds) stabilize the protein fold. Interactions could be intrachain, i.e.
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The side-chain of amino acids and the nature of interactions in the backbone restrict these two angles, and thus, the visualization of allowed conformations could be performed based on the Ramachandran plot. A high quantity of amino acids allocated in no permissive positions of the chart is an indication of a low-quality modeling.
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Since enthalpy is usually more important, entropy can often be ignored. This isn't always the case; if the difference in enthalpy is small, entropy can have a larger effect on the equilibrium. For example, n-butane has two possible conformations, anti and gauche. The anti conformation is more stable by 0.9 kcal mol−1.
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Torsional strain is the resistance to bond twisting. In cyclic molecules, it is also called Pitzer strain. Torsional strain occurs when atoms separated by three bonds are placed in an eclipsed conformation instead of the more stable staggered conformation. The barrier of rotation between staggered conformations of ethane is approximately 2.9 kcal mol−1.
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Proteins are chains of amino acids joined together by peptide bonds. Many conformations of this chain are possible due to the rotation of the chain about each Cα atom. It is these conformational changes that are responsible for differences in the three dimensional structure of proteins. Each amino acid in the chain is polar, i.e.
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Xenon is an effective inhibitor of plasma membrane Ca2+ ATPase. Xenon inhibits Ca2+ ATPase by binding to a hydrophobic pore within the enzyme and preventing the enzyme from assuming active conformations. Xenon is a competitive inhibitor of the serotonin 5-HT3 receptor. While neither anesthetic nor antinociceptive, this reduces anesthesia-emergent nausea and vomiting.
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A common challenge in refinement of crystal structures results from crystallographic disorder. Disorder can take many forms but in general involves the coexistence of two or more species or conformations. Failure to recognize disorder results in flawed interpretation. Pitfalls from improper modeling of disorder are illustrated by the discounted hypothesis of bond stretch isomerism.
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Mad2 is capable of forming multimers and adopts at least two structural conformations. Open Mad2 differs from closed Mad2 in the positioning of the 50 residue C-terminal segment. This “safety belt” is held tightly against the right side of the protein in the open conformation. Upon loosening, the safety belt can be re-positioned around a binding partner.
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The conformationally flexible C-terminal arms are shown here in conformations compatible with binding to neighboring molecules. Superposed is a fragment of the polyomavirus VP2 protein (white), which binds to a pentamer oriented toward the central cavity. VP1 is from ; VP2 is from . The VP1 protein monomer is primarily composed of beta sheets folded into a jelly roll fold.
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FoldX is a protein design algorithm that uses an empirical force field. It can determine the energetic effect of point mutations as well as the interaction energy of protein complexes (including Protein-DNA). FoldX can mutate protein and DNA side chains using a probability-based rotamer library, while exploring alternative conformations of the surrounding side chains.
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Native-like conformations are then selected from these decoys using scoring functions as well as conformer clustering. High-resolution refinement is sometimes used as a final step to fine-tune native-like structures. There are two major classes of scoring functions. Physics-based functions are based on mathematical models describing aspects of the known physics of molecular interaction.
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Benjamin Cummings. Fischer projections should not be confused with Lewis structures, which do not contain any information about three dimensional geometry. Wedge- and-dash notation is used to represent the stereochemistry of most classes of organic compounds, with Newman projections being used to depict specific conformations of rotatable bonds of organic molecules (including but not limited to carbohydrates).
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AraC undergoes conformational change upon arabinose- binding, in which, it has two distinct conformations. The conformation is purely determined by the binding of allosteric inducer arabinose. AraC can also negatively autoregulate its own expression when the concentration of AraC becomes too high. AraC synthesis is repressed through binding of dimeric AraC to the operator region (araO1).
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The effects of TMAO on the backbone and charged residues of peptides are found to stabilize compact conformations, whereas effects of TMAO on nonpolar residues lead to peptide swelling. This suggests competing mechanisms of TMAO on proteins, which accounts for hydrophobic swelling, backbone collapse, and stabilization of charge-charge interactions. These mechanisms are observed in Trp cage.
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More recent techniques enable researchers to track transitions in the conformations of macromolecular ions during the gas phase. A short pulse of ions is introduced into a drift tube by electrospray ionization. Structures separate based on differences in their mobilities. By exposing specific states to energizing collisions, new structures can be established and tracked through different conformational changes.
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ADP ribosylation factor (ARF) is a GTPase involved in membrane traffic. There are 6 mammalian ARFs which are regulated by over 30 guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). ARF is post-translationally modified at the N-terminus by the addition of the fatty acid myristate. ARF cycles between GTP and GDP-bound conformations.
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Cephaloridine is a cephalosporin compound with pyridinium-1-ylmethyl and 2-thienylacetamido side groups. The molecular nucleus, of which all cephalosporins are derivatives, is A3-7-aminocephalosporanic acid. Conformations around the β-lactam rings are quite similar to the molecular nucleus of penicillin, while those at the carboxyl group exocyclic to the dihydrothiazine and thiazolidine rings respectively are different.
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These are used to determine dynamical pathways between different protein conformations using Monte Carlo methods. Proteins are stable enough to maintain a three-dimensional structure, but flexible enough for biological function. The aim of this research work is to find underlying principles and unifying concepts, to better understand the evolution and function of proteins and protein complexes.
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An RNA pseudoknot structure. For example, the RNA component of human telomerase. A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. Pseudoknots fold into knot-shaped three-dimensional conformations but are not true topological knots.
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Cyclooctatetraene in its native "tub-shaped" conformation. Early studies demonstrated that COT did not display the chemistry of an aromatic compound. Then, early electron diffraction experiments concluded that the C-C bond distances were identical. However, X-ray diffraction data from H. S. Kaufman demonstrated cyclooctatetraene to adopt several conformations and to contain two distinct C–C bond distances.
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Proteins are polymers that are made up of amino acid chains linked with peptide bonds. They have four distinct levels of structure: primary, secondary, tertiary, and quaternary. Primary structure refers to the amino acid backbone sequence. Secondary structure focuses on minor conformations that develop as a result of the hydrogen bonding between the amino acid chain.
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Unlike the add adenine riboswitch, the pbuE adenine riboswitch appears to exist in one of two stable conformations. Binding of adenine causes the formation of an antiterminator, thus allowing transcription to finish to completion. In the absence of adenine, the aptamer domain of the riboswitch instead associates with the riboswitch expression platform, leading to transcription termination.
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The crystallization of the exon junction complex has revealed the structural organization of its protein components. The core of the complex is elongated with an overall dimension of 99Å by 67Å by 54Å. It is organized around the eIF4AIII factor. The factor itself consists of two different types of conformations around the mRNA: closed and open.
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In contrast to leukocytes which have monomeric Kv1.3 channels, macrophages have heterotetrameric Kv1.3/Kv1.5 channels. These heterotetramers plays a role in regulating the membrane potential of macrophages on different stages of macrophage activation by lymphocytes. Potassium channels are involved in leukocyte activation by calcium. The possible different conformations of these Kv1.3 and 1.5 complexes can affect the immune response.
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The principal idea is to develop superior physico-chemical properties of the API while holding the properties of the drug molecule itself constant. Cocrystal structures have also become a staple for drug discovery. Structure-based virtual screening methods, such as docking, makes use of cocrystal structures of known proteins or receptors to elucidate new ligand-receptor binding conformations.
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This makes experimental determination of important quantities such as the root mean square end-to-end distance or the radius of gyration much simpler. Additionally, the theta condition is also satisfied in the bulk amorphous polymer phase. Thus, the conformations adopted by polymers dissolved in theta solvents are identical to those adopted in bulk polymer polymerization .
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2.Methylcholanthrene mechanism 3-MC has an inhibitory function in a dimethylnitrosamine demethylase process in rat livers. Inhibition could happen on by interfering in demethylase conformations or by interfering in synthesis and/or degradation of demethylase. Experiments showed that the Km doesn’t change after 3-MC treatment. This strongly indicates that enzyme affinity is not influenced by 3-MC.
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The stereochemical result of a given reaction on a macrocycle capable of adopting several conformations can be modeled by a Curtin-Hammett scenario. In the diagram below, the two ground state conformations exist in an equilibrium, with some difference in their ground state energies. Conformation B is lower in energy than conformation A, and while possessing a similar energy barrier to its transition state in a hypothetical reaction, thus the product formed is predominantly product B (P B) arising from conformation B via transition state B (TS B). The inherent preference of a ring to exist in one conformation over another provides a tool for stereoselective control of reactions by biasing the ring into a given configuration in the ground state. The energy differences, ΔΔG‡ and ΔG0 are significant considerations in this scenario.
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B-DNA is the most common form of DNA in vivo and is a more narrow, elongated helix than A-DNA. Its wide major groove makes it more accessible to proteins. On the other hand, it has a narrow minor groove. B-DNA's favored conformations occur at high water concentrations; the hydration of the minor groove appears to favor B-DNA.
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Once palytoxin is bound to the pump, it flips constantly between open and normal conformations. The open conformation is more likely (over 90% probability). If palytoxin detaches, the pump will return to closed conformation. In open conformation, millions of ions diffuse through the pump per second, whereas only about one hundred ions per second are transported through a normally functioning transporter.
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Two chair conformations of cyclohexane. The entirety of axial positions become equatorial, and vice versa, upon ring flip. In organic chemistry, a ring flip (also known as a ring inversion or ring reversal) is the interconversion of cyclic conformers that have equivalent ring shapes (e.g., from a chair conformer to another chair conformer) that results in the exchange of nonequivalent substituent positions.
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Figure 9: Potential relationship based on isolobal principles. Uses of the isolobal analogy include providing a shortcut to understanding electronic structure, predicting reactivity and reaction mechanisms, and a method of classifying molecules. Applications are typically utilized to make connections between well-known systems and less familiar systems. For example, the possibility of unsynthesized compounds can be imagined from those of known molecular conformations.
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Formylation is a post translational modification which occurs on lysine residues. ε-Formylation is one of many post-translational modifications that occur on histone proteins, which been shown to modulate chromatin conformations and gene activation. Formylation of lysine can compete with acetylation as a post-translational modification. Formylation has been identified on the Nε of lysine residues in histones and proteins.
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Kinesins are structurally related to G proteins, which hydrolyze GTP instead of ATP. Several structural elements are shared between the two families, notably the Switch I and Switch II domain. Mobile and self-inhibited conformations of kinesin-1. Self-inhibited conformation:IAK region of the tail (green) binds to motor domains (yellow and orange) to inhibit the enzymatic cycle of kinesin-1.
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Radiation of methoxyvinyl protons in free enone and in enone complexed with monodentate Ti(IV) show s-cis and s-trans conformations, while radiation of the enone in a bidentate Ti(IV) complex showed predominantly s-trans conformers. In 2003, this group extended the allylation strategy using this bidentate catalyst to ketones.Kii, S., Maruoka, K., Chirality, 2003, 15, 68-70.
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As a result, multiple crystal structures can be obtained with the same molecule but in different conformations. The rarest form of polymorphism arises from the differences in the primary synthon and this type of polymorphism is called as synthon polymorphism. With the growth in research in the cocrystals in recent times, it is observed that cocrystals are also prone to polymorphism.
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Juan added additional bloodlines including the Welsh Pony, Shetland pony, and small Thoroughbreds. With considerable inbreeding he was able to gain consistently small size within the herd. The South African Miniature Horse was developed in South Africa and has a wide range of conformations represented in its population. Some resemble miniature Arabians, while others appear to be scaled-down versions of draft horses.
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The different structure that is resulted by the mutation in the muconate lactonizing enzyme is Cl-muconate lactonizing enzyme. Cl-muconate lactonizing enzyme has two types of conformations :- open and closed. The mutation results in the switch of an amino acid to Ser99 and it hydrogen bonds to Gly48. The structure that results due this has a closed active site.
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A helix hairpin, also known as an alpha-alpha hairpin, is composed of two antiparallel alpha helices connected by a loop of two or more residues. True to its name, it resembles a hairpin. A longer loop has a greater number of possible conformations. If short strands connect the helices, then the individual helices will pack together through their hydrophobic residues.
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The utility of A-values can be generalized for use outside of cyclohexane conformations. A-values can help predict the steric effect of a substituent. In general, the larger a substituent's A-value, the larger the steric effect of that substituent. A methyl group has an A-value of 1.74 while tert-butyl group has an A-value of ~5.
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5019–5027 The branched isomers are more stable (have lower heat of formation and heat of combustion) than n-pentane. The difference is 1.8 kcal/mol for isopentane, and 5 kcal/mol for neopentane.From the values listed at Standard enthalpy change of formation (data table). Rotation about two central single C-C bonds of n-pentane produces four different conformations.
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The TRPV6 protein is constitutive with a single-channel conductance of 42-58 ps. At low Ca2+ concentrations, a single Ca2+ ion binds in the selectivity filter formed by D541 and permits Na+ permeation. At high Ca2+ concentration, Ca2+ permeation occurs by a knock-off mechanism that involves the formation of short-lived conformations involving binding of three Ca2+ ions to residue D541.
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Figure 3. Gating mechanism of TRPV6. Shown are the closed and open conformations of the S6 transmembrane domain of TRPV6. The opening of the lower gate is caused by an α- to the π-helical transition of the transmembrane helix S6 at residue A566, which induces the intracellular part of S6 bends by about 11º and rotates by about 100º.
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Krueger KM, Witte DG, Ireland-Denny L, Miller TR, Baranowski JL, Buckner S, Milicic I, Esbenshade TA, Hancock AA. G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations. Journal of Pharmacology and Experimental Therapeutics. 2005 Jul;314(1):271-81. Arrang JM, Morisset S, Gbahou F. Constitutive activity of the histamine H3 receptor.
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In polyubiquitin-C, the C-terminus of a given ubiquitin molecule is covalently conjugated to either the N-terminal residue or one of seven lysine residues of another ubiquitin molecule. Different linking of ubiquitin chains results in distinct conformations. There are 8 linkage types of polyubiquitin-C, and each type possesses the linkage-dependent dynamics and a linkage-specific conformation.
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240px Conformational analysis of medium rings begins with examination of cyclooctane. Spectroscopic methods have determined that cyclooctane possesses three main conformations: chair-boat, chair-chair, and boat-boat. Cyclooctane prefers to reside in a chair-boat conformation, minimizing the number of eclipsing ethane interactions (shown in blue), as well as torsional strain.Petasis, N. A.; Patane, M.A. Tetrahedron 1992, 48, 5757-5821.
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Schematic showing two possible conformations of the lipids at the edge of a pore. In the top image the lipids have not rearranged, so the pore wall is hydrophobic. In the bottom image some of the lipid heads have bent over, so the pore wall is hydrophilic. Edge energy is the energy per unit length of a free edge contacting water.
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The combination of high-resolution NMR-based analysis of RNA structures and time- resolved ligand-induced refolding of RNAs by caging distinct conformations together with pulsed electron paramagnetic resonance methods (PELDOR) after base-specific spin-labeling and ultrafast laser spectroscopy of RNA dynamics has led to the description of the structural dynamics of several RNAs. CEF scientists showed that the regulation mechanism of the adenine-sensing riboswitch of the human pathogenic bacterium Vibrio vulnificus is notably different from a two-state switch mechanism in that it involves three distinct stable conformations. This translational adenine-sensing riboswitch represented the first example of a temperature-compensated regulatory RNA element . The composition and structure of the HIV TAR RNA-Ligand complex was analyzed by LILBID and NMR , leading to a description of the complexity of peptide binding sites in RNAs.
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Alkanes generally have minimum energy when the C–C–C angles are close to 110 degrees. Conformations of the cyclohexane molecule with all six carbon atoms on the same plane have a higher energy, because some or all the C–C–C angles must be far from that value (120 degrees for a regular hexagon). Thus the conformations which are local energy minima have the ring twisted in space, according to one of two patterns known as chair (with the carbons alternately above and below their mean plane) and boat (with two opposite carbons above the plane, and the other four below it). If the energy barrier between two conformational isomers is low enough, it may be overcome by the random inputs of thermal energy that the molecule gets from interactions with the environment or from its own vibrations.
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Traditional knot theory models a knot as a simple closed loop in three-dimensional space. Such a knot has no thickness or physical properties such as tension or friction. Physical knot theory incorporates more realistic models. The traditional model is also studied but with an eye toward properties of specific embeddings ("conformations") of the circle. Such properties include ropelength and various knot energies (O’Hara 2003).
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Binding to the nicotinic receptor Shorter molecules like acetylcholine need two molecules to activate the receptor, one at each receptive site. Decamethonium congeners, which prefer straight line conformations (their lowest energy state), usually span the two receptive sites with one molecule (binding inter-site). Longer congeners must bend when fitting receptive sites. The greater energy a molecule needs to bend and fit usually results in lower potency.
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Neutral networks exist in fitness landscapes since proteins are robust to mutations. This leads to extended networks of genes of equivalent function, linked by neutral mutations. Proteins are resistant to mutations because many sequences can fold into highly similar structural folds. A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding).
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When all of the isoprene units in a network chain have been forced to reside in just a few extended rotational conformations, the chain becomes taut. It may be regarded as sensibly straight, except for the zigzag path that the C-C bonds make along the chain contour. However, further extension is still possible by bond distortions, e.g., bond angle increases, bond stretches and dihedral angle rotations.
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Gairo's territory is also famous for its natural beauties. Perd'e Liana, for instance, is one of the most important and evocative morphological conformations in Sardinia. It is a natural monument constituted by a vertical tower, a so-called heel or "tonneri" in Sardinian, that races skywards. At 1293 m, it is one of the best known natural monuments on the island for its strange appearance.
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When the inhibitory signals are prevented, the motor neurons are more easily activated and the victim will have spastic muscle contractions, resulting in death by asphyxiation.Waring, R. H.; Steventon, G. B.; Mitchell, S. C. Molecules of death, Imperial College Press, 2007 Strychnine binds the Aplysia californica acetylcholine binding protein (a homolog of nicotinic receptors) with high affinity but low specificity, and does so in multiple conformations.
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The continuum representation of solvent also significantly improves the computational speed and reduces errors in statistical averaging that arise from incomplete sampling of solvent conformations, so that the energy landscapes obtained with implicit and explicit solvent are different. Although the implicit solvent model is useful for simulations of biomolecules, this is an approximate method with certain limitations and problems related to parameterization and treatment of ionization effects.
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Cyclic molecules often exist in much more rigid conformations than their linear counterparts. Even very large macrocycles like erythromycin exist in defined geometries despite having many degrees of freedom. Because of these properties, it is often easier to achieve asymmetric induction with macrocyclic substrates rather than linear ones. Early experiments performed by W. Clark StillStill, W. C.; Galynker, I. Tetrahedron 1981, 37, 3981-3996.
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Deletion breakpoints frequently occur within or near regions showing non-canonical (non-B) conformations, namely hairpins, cruciforms and cloverleaf-like elements. Moreover, there is data supporting the involvement of helix-distorting intrinsically curved regions and long G-tetrads in eliciting instability events. In addition, higher breakpoint densities were consistently observed within GC-skewed regions and in the close vicinity of the degenerate sequence motif YMMYMNNMMHM.
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Conformations adopted by saccharide molecules in response to the physical forces arising from their bonding and nonbonding electrons, modified by the molecule's interactions with its aqueous or other solvent environment, strongly influence their reactivity with and recognition by other molecules (processes which in turn can alter conformation). Chemical transformations and biological signalling mediated by conformation-dependent molecular recognition between molecules underlie all essential processes in living organisms.
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Two models provide an explanation of their structure, the classical and the non-classical view. The classical view (Figure 1.a) involves a fast- equilibrating system in which a hydrogen atom rapidly shifts between two adjacent carbon atoms. In this model, fast equilibrium results from a low energy barrier between the two conformations of the molecule, and each conformer has a localized positive charge.
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The resistance to proteolysis shown by CRDs 4 and 5 suggests physical interactions between the two domains does occur, thereby supporting the existence of this U-shaped conformation. It is thought that transitions between these two conformations occur in a pH- dependent manner, regulating ligand selectivity and release during endocytosis. The lower, more acidic pH of early endosomes is thought to be responsible for ligand release.
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Heterocyclic analogs of cyclohexane are pervasive in sugars, piperidines, dioxanes, etc. They exist generally follow the trends seen for cyclohexane, i.e. the chair conformer being most stable. The axial- equatorial equilibria (A values) are however strongly affected by the replacement of a methylene by O or NH. Illustrative are the conformations of the glucosides. 1,2,4,5-Tetrathiane ((SCH2)3) lacks the unfavorable 1,3-diaxial interactions of cyclohexane.
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In 2010, Feihe Huang et al.Zhang, Z.; Xia, B.; Han, C.; Yu, Y.; Huang, F. Syntheses of Copillar[5]arenes by Co-oligomerization of Different Monomers, Organic Letters, 2010, 12, 3285-3287. introduced three new ways to synthesize copillararenes, which are composed of different repeating units. It is easier to selectively functionalize copillararenes, helping to generate interesting physical properties, conformations, and host–guest binding interactions.
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C-DNA also known as C form DNA. It is one of the many possible double helical structures of DNA. This form of DNA can be observed at some conditions such as relatively low humidity and the presence of certain ions, such as Li+ or Mg2+. Recent research suggests that both C-DNA and B-DNA consist of two distinct nucleotide conformations, B-I and B-II.
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RNA has many purposes throughout the cell including many important steps in gene expression. Various conformations of the non-Watson-Crick base pairs allow for a multitude of biological functions such as mRNA splicing, siRNA, transport, protein recognition, protein binding, and translation. One example of a biological application of non-canonical base pairs in the kink turn. A kink-turn is found throughout many functional RNA species.
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Native-like amyloid fibrils in which native β-sheet containing proteins maintain their native-like structure in the fibrils have also been proposed. One complicating factor in studies of amyloidogenic polypeptides is that identical polypeptides can fold into multiple distinct amyloid conformations. This phenomenon is typically described as amyloid polymorphism. It has notable biological consequences given that it is thought to explain the prion strain phenomenon.
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Lehn and coworkers in Helv. Chim. Acta, 2003, 86, 1598–1624. Dynamic view of an alpha-beta foldamer In chemistry, a foldamer is a discrete chain molecule or oligomer that folds into a conformationally ordered state in solution. They are artificial molecules that mimic the ability of proteins, nucleic acids, and polysaccharides to fold into well-defined conformations, such as helices and β-sheets.
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Scheme 1. CyclophanesA cyclophane is a hydrocarbon consisting of an aromatic unit (typically a benzene ring) and an aliphatic chain that forms a bridge between two non-adjacent positions of the aromatic ring. More complex derivatives with multiple aromatic units and bridges forming cagelike structures are also known. Cyclophanes are well-studied in organic chemistry because they adopt unusual chemical conformations due to build-up of strain.
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The crystal structure of Re2(CO)10 is relatively well known. The compound consists of a pair of square pyramidal Re(CO)5 units linked by a Re- Re bond. There are two different conformations that can occur: staggered and eclipsed. The eclipsed conformation occurs about 30% of the time, producing a D4h point group, but the staggered form, with point group D4d, is more stable.
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The complete structures for two of the four B toxins (B-II and B-IV) have been determined . Toxin B-II differs from B-IV in that the secondary structure of Toxin B-II contains about 15-20% less α-helixes than B-IV due to the differences in the primary structure of the two proteins; amino acids Ala in position 3, Ala in position 7 and Ala in position 8 in B-IV are substituted by amino acids Ser, Gly and Ser in B-II respectively. No homology is displayed with other sodium channel selective toxins, such as scorpion and sea anemone venom toxins, despite being similar in size, basicity, and degree of cross-linking. The secondary structures of scorpion and anemone toxins are largely organized into β-sheet conformations, while the secondary structures of B toxins organize in α-helical conformations Howell, M. L., Blumenthal, K. M. (1991).
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In this way, chaperones do not actually increase the rate of individual steps involved in the folding pathway toward the native structure; instead, they work by reducing possible unwanted aggregations of the polypeptide chain that might otherwise slow down the search for the proper intermediate and they provide a more efficient pathway for the polypeptide chain to assume the correct conformations. Chaperones are not to be confused with folding catalysts, which actually do catalyze the otherwise slow steps in the folding pathway. Examples of folding catalysts are protein disulfide isomerases and peptidyl-prolyl isomerases that may be involved in formation of disulfide bonds or interconversion between cis and trans stereoisomers, respectively. Chaperones are shown to be critical in the process of protein folding in vivo because they provide the protein with the aid needed to assume its proper alignments and conformations efficiently enough to become "biologically relevant".
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Elongated Mad1 monomers are tightly held together by a parallel coiled-coil involving the N-terminal alpha helices. The Mad1 chains point away from the coiled-coil towards their Mad2 ligands forming two sub-complexes with Mad2. The segment between alpha helices 1 and 2 contains the Mad2 binding domain. The first part of this binding domain is flexible and adopts different conformations giving rise to an asymmetric complex.
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Some of these characteristics hypothetically can be related to a change of binding constants with relevant antibodies. The S-protein of SARS- CoV-1, MERS-CoV and SARS-CoV-2 have at least two conformations that are antigenically different. S-protein receptor binding domain (RBD) in S1 subunit can be in a receptor inaccessible (closed) or accessible (open) state. Therefore the RBD can be in up or down positions.
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Ensembles are models consisting of a set of conformations that together attempt to describe the structure of a flexible protein. Even though the degree of conformational freedom is extremely high, flexible/disordered protein generally differ from fully random coil structures. The main purpose of these models is to gain insights regarding the function of the flexible protein, extending the structure-function paradigm from folded proteins to intrinsically disordered proteins.
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Both actin and tubulin bind to CCT in open conformations in the absence of ATP. In actin's case, two subunits are bound during each conformational change, whereas for tubulin binding takes place with four subunits. Actin has specific binding sequences, which interact with the δ and β-CCT subunits or with δ-CCT and ε-CCT. After AMP-PNP is bound to CCT the substrates move within the chaperonin's cavity.
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Tricyclobutabenzene is an aromatic hydrocarbon consisting of a benzene core with three cyclobutane rings fused onto it. This compound and related compounds are studied in the laboratory because they are often displaying unusual conformations and because of their unusual reactivity. Tricyclobutabenzenes are isomers of radialenes and form an equilibrium with them. The parent tricyclobutabenzene (C12H12) was first synthesised in 1979Tricyclobutabenzene Wutichai Nutakul, Randolph P. Thummel, Austin D. Taggart J.
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In this model, a subunit does not automatically change conformation upon ligand binding (as in the KNF model), nor do all subunits in a complex change conformations together (as in the MWC model). Conformational changes are stochastic with the likelihood of a subunit switching states depending on whether or not it is ligand bound and on the conformational state of neighbouring subunits. Thus, conformational states can "spread" around the entire complex.
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This algorithm is used to define domains in the FSSP domain database. Swindells (1995) developed a method, DETECTIVE, for identification of domains in protein structures based on the idea that domains have a hydrophobic interior. Deficiencies were found to occur when hydrophobic cores from different domains continue through the interface region. RigidFinder is a novel method for identification of protein rigid blocks (domains and loops) from two different conformations.
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The constricted nature of the interior of the molecular complex strongly favors compact molecular conformations of the substrate protein. Free in solution, long-range, non-polar interactions can only occur at a high cost in entropy. In the close quarters of the GroEL complex, the relative loss of entropy is much smaller. The method of capture also tends to concentrate the non-polar binding sites separately from the polar sites.
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Trimers aggregate in pairs to form hexamers (αβ)6, sometimes assisted with additional linker proteins. Each phycobilisome rod generally has two or more phycocyanin hexamers. Despite the overall similarity in structure and assembly of phycobiliproteins, there is a large diversity in hexamer and rod conformations, even when only considering phycocyanins. On a larger scale phycocyanins also vary in crystal structure, although the biological relevance of this is debatable.
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Pyranose and furanose forms can exist in different conformers and one can interconvert between the different conformations if an energy requirement is met. For the furanose system there are two possible conformers: twist (T) and envelope (E). In the pyranose system five conformers are possible: chair (C), boat (B), skew (S), half-chair (H) or envelope (E). In all cases there are four or more atoms that make up a plane.
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Activation of tTG has been shown to be accompanied by large conformational changes, switching from a compact (inactive) to an extended (active) conformation. (see Figure 3) Figure 3: Compact (inactive) and extended (active) conformations of tTGIn the extracellular matrix, TG2 is "turned off", due primarily to the oxidizing activity of endoplasmic reticulum protein 57 (ERp57). Thus, tTG is allosterically regulated by two separate proteins, Erp57 and TRX-1. (See Figure 4).
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The study of the energetics between different conformations is referred to as conformational analysis. It is useful for understanding the stability of different isomers, for example, by taking into account the spatial orientation and through-space interactions of substituents. In addition, conformational analysis can be used to predict and explain product selectivity, mechanisms, and rates of reactions. Conformational analysis also plays an important role in rational, structure-based drug design.
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The fact that pdxJ binds substrates through their phosphate groups explains a previously discovered specificity for the substrates over their respective non-phosphorylated alcohols. pdxJ exhibits several different conformations, depending on the substrates or substrate analogs bound. The first state, exhibited when pdxJ has either pyridoxine-5'-phosphate or no substrates bound, is classified as the "open" conformation. This conformation is characterized by an active site freely accessible by solvent.
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Antigenic specificity is the ability of the host cells to recognize an antigen specifically as a unique molecular entity and distinguish it from another with exquisite precision. Antigen specificity is due primarily to the side-chain conformations of the antigen. It is measurable and need not be linear or of a rate-limited step or equation. Both T cells and B cells are cellular components of adaptive immunity.
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The morpheein model of allostery exemplified by PBGS adds an additional layer of understanding to potential mechanisms for regulation of protein function and complements the increased focus that the protein science community is placing on protein structure dynamics. This model illustrates how the dynamics of phenomena such as alternate protein conformations, alternate oligomeric states, and transient protein-protein interactions can be harnessed for allosteric regulation of catalytic activity.
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Watson-Crick canonical base pairing is not the only edge-to-edge conformation possible for the nucleotide since non-canonical pairing can take place as well. Sugar-phosphate backbone has an ionic character, which makes the bases sensitive to their environment, leading to conformational changes, such as non-canonical pairing. There are various methods of prediction for these conformations, such as NMR structure determination and X-ray crystallography.
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The polysulfide anions form chains with S---S bond distances around 2 Å in length. The chains adopt skewed conformations. In the solid state, these salts are dense solids with strong association of the sodium cations with the anionic termini of the chains.Rosén, E.; Tegman, R. "Preparative and X - ray powder diffraction study of the polysulfides Na2S2, Na2S4 and Na2S5" Acta Chemica Scandinavica 1988, volume 25, pp 3329-3336.
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The conformation assumed by a polymer chain in dilute solution can be modeled as a random walk of monomer subunits using a freely jointed chain model. However, this model does not account for steric effects. Real polymer coils are more closely represented by a self-avoiding walk because conformations in which different chain segments occupy the same space are not physically possible. This excluded volume effect causes the polymer to expand.
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Similar principles guide the lowest energy conformations of larger ring systems. Along with the acyclic stereocontrol principles outlined below, subtle interactions between remote substituents in large rings, analogous to those observed for 8-10 membered rings, can influence the conformational preferences of a molecule. In conjunction with remote substituent effects, local acyclic interactions can also play an important role in determining the outcome of macrocyclic reactions.Deslongchamps, P. Pure Appl. Chem.
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Macrocyclic rings containing sp2 centers display a conformational preference for the sp2 centers to avoid transannular nonbonded interactions by orienting perpendicular to the plan of the ring. Clark W. Still proposed that the ground state conformations of macrocyclic rings, containing the energy minimized orientation of the sp2 center, display one face of an olefin outwards from the ring.Still, W.C.; Novack, V.J. J. Am. Chem. Soc. 1984, 106, 1148-1149.
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Because cadherins are Ca2+ dependent, they have five tandem extracellular domain repeats that act as the binding site for Ca2+ ions. Their extracellular domain interacts in two separate trans dimer conformations: strand-swap dimers (S-dimers) and X-dimers. To date, over 100 types of cadherins in humans have been identified and sequenced. The functionality of cadherins relies upon the formation of two identical subunits, known as homodimers.
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The open and closed conformations refer to the state of the DNA and whether the template strand has been separated from the non-template strand within the PIC. The place at which the DNA opens to form the bubble lies above a tunnel that is lined by the B-core, B-linker and B-reader as well as parts of RNA polymerase II. The B linker is found directly aligned with the point at which the DNA opens and in the open complex it is found between the two DNA strands, suggesting that it has a role in promoter melting, but it does not have a role in the catalytic RNA synthesis. Although TFIIB keeps a similar structure in both conformations some of the intramolecular interactions between the core and the B reader are disrupted upon DNA opening. After DNA melting the transcription initiator (Inr) must be located on the DNA so the TSS can be identified by the RNA polymerase II and transcription can begin.
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Normally folded proteins have to unfold partially before aggregation can take place through one of these mechanisms. In some cases, however, folded proteins can aggregate without crossing the major energy barrier for unfolding, by populating native-like conformations as a consequence of thermal fluctuations, ligand release or local unfolding occurring in particular circumstances. In these native-like conformations, segments that are normally buried or structured in the fully folded and possessing a high propensity to aggregate become exposed to the solvent or flexible, allowing the formation of native-like aggregates, which convert subsequently into nuclei and fibrils. This process is called ‘native-like aggregation’ (green arrows in the figure) and is similar to the ‘nucleated conformational conversion’ model. A more recent, modern and thorough model of amyloid fibril formation involves the intervention of secondary events, such as ‘fragmentation’, in which a fibril breaks into two or more shorter fibrils, and ‘secondary nucleation’, in which fibril surfaces (not fibril ends) catalyze the formation of new nuclei.
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A roadmap G = (V,E) is a directed graph. Each vertex v is a randomly sampled conformation in C. Each (directed) edge from vertex vi to vertex vj carries a weight Pij , which represents the probability that the molecule will move to conformation vj , given that it is currently at vi. The probability Pij is 0 if there is no edge from vi to vj. Otherwise, it depends on the energy difference between conformations.
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Each glucose isomer is subject to rotational isomerism. Within the cyclic form of glucose, rotation may occur around the O6-C6-C5-O5 torsion angle, termed the ω-angle, to form three staggered rotamer conformations called gauche-gauche (gg), gauche-trans (gt) and trans-gauche (tg).For methyl α-D-glucuopyranose at equilibrium, the ratio of molecules in each rotamer conformation is reported to be 57% gg, 38% gt, and 5% tg. See .
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This suggests that NS5A inhibitors act on dimers of NS5A. A number of modeling studies have shown that daclatasvir, which is an NS5A inhibitor, only binds to the "back-to-back" NS5A dimer and that the binding has to be symmetrical. Other modeling studies have shown that binding to other conformations of NS5A might be possible, as well as asymmetrical binding. Research has shown that daclatasvir's target is most likely domain I of NS5A.
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At pH 4 however, KcsA undergoes millisecond-timescale conformational exchanges filter permeating and nonpermeating states and between the open and closed conformations of the M2 helices. While these distinct conformational changes occur in separate regions of the channel, the molecular behavior of each region is linked by both electrostatic interactions and allostery. The dynamics of this exchange stereochemical configurations in the filter provides the physical basis for simultaneous K+ conductance and gating.
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Clemmer has identified fundamental relationships between charge states and structures, and has shown that a single charge state can exist in more than one conformation in gaseous states. Such techniques can be used for the study of both proteins and peptides. In early work, Clemmer showed that multiple conformations of the hemeprotein cytochrome c could be differentiated based on their mobilities. In addition, the mobility of different chiral isomers was related to their protein folding.
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Magnetoelastic filaments are one-dimensional composite structures that exhibit both magnetic and elastic properties. Interest in these materials tends to focus on the ability to precisely control mechanical events using an external magnetic field. Like piezoelectricity materials, they can be used as actuators, but do not need to be physically connected to a power source. The conformations adopted by magnetoelastic filaments are dictated by the competition between its elastic and magnetic properties.
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Schematic showing two possible conformations of the lipids at the edge of a pore. In the top image the lipids have not rearranged, so the pore wall is hydrophobic. In the bottom image some of the lipid heads have bent over, so the pore wall is hydrophilic. For cellular organisms, the transport of specific molecules across compartmentalizing membrane barriers is essential in order to exchange content with their environment and with other individuals.
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The steric bite angle effect involves the steric interactions between ligands or between a ligand and a substrate. The electronic bite angle effect, on the other hand, relates to the electronic changes that occur when the bite angle is modified. This effect is sensitive to the hybridization of metal orbitals. This flexibility range accounts for the diverse conformations of the ligand with energies slightly above the strain energy of the natural bite angle.
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Chymopapain's structure was solved by X-ray diffraction techniques. Analysis of this structure showed chymopapain to have 7 alpha helix regions, 10 beta sheet regions and 2 loop turns. These 2 turns are the main difference between chymopapain's structure and other papaya proteinase proteins such as papain or caricain, which have similar conformations. Besides, chymopapain presents 3 disulfide bonds as post- traducional modifications stablished between residues 156-197, 190-229 and 287-338.
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Further transformations of the resulting conformationally restricted, benzylic anion or cation involve the approach of reagents exo to the chromium fragment. Thus, benzylic functionalization reactions of planar chiral chromium arene complexes are highly diastereoselective. Additionally, the chromium tri(carbonyl) fragment can be used as a blocking element in addition reactions to ortho-substituted aromatic aldehydes and alkenes. An ortho substituent is necessary in these reactions to restrict conformations available to the aldehyde or alkene.
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The methyl group prefers the equatorial orientation. The preference of a substituent towards the equatorial conformation is measured in terms of its A value, which is the Gibbs free energy difference between the two chair conformations. A positive A value indicates preference towards the equatorial position. The magnitude of the A values ranges from nearly zero for very small substituents such as deuterium, to about for very bulky substituents such as the tert-butyl group.
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In structural biology, ambiguity has been recognized as a problem for studying protein conformations. The analysis of a protein three-dimensional structure consists in dividing the macromolecule into subunits called domains. The difficulty of this task arises from the fact that different definitions of what a domain is can be used (e.g. folding autonomy, function, thermodynamic stability, or domain motions), which sometimes results in a single protein having different—yet equally valid—domain assignments.
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Some of the substrate-bound conformations bear high similarity to the substrate-free ones, but they are not entirely identical, particularly in the AAA-ATPase module. Prior to the 26S assembly, the 19S regulatory particle in a free form has also been observed in seven conformational states. Notably, all these conformers are somewhat different and present distinct features. Thus, the 19S regulatory particle can sample at least 20 conformational states under different physiological conditions.
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The (3R,4R) isomer is the agonist, while (3S,4S) is antagonist.Froimowitz M, Cody V. Absolute configurations and conformations of the opioid agonist and antagonist enantiomers of picenadol. Chirality. 1995;7(7):518-25. This means that the racemic mix of the two enantiomers is a mixed agonist-antagonist, with relatively low abuse potential, and little of the κ-opioid activity that tends to cause problems with other opioid mixed agonist-antagonists such as pentazocine.
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The more recent developments of vibrational circular dichroism (VCD) techniques for proteins, currently involving Fourier transform (FT) instruments, provide powerful means for determining protein conformations in solution even for very large protein molecules. Such VCD studies of proteins are often combined with X-ray diffraction of protein crystals, FT-IR data for protein solutions in heavy water (D2O), or ab initio quantum computations to provide unambiguous structural assignments that are unobtainable from CD.
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Protein mutation tolerance is the product of two main features: the structure of the genetic code and protein structural robustness. Proteins are resistant to mutations because many sequences can fold into highly similar structural folds. A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding). This is achieved by a distributed, internal network of cooperative interactions (hydrophobic, polar and covalent).
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In contrast, the closed conformation chains have interfaces with interacting residues. Altering the chain conformations exposes and conceals different parts of the ubiquitin protein, and the different linkages are recognized by proteins that are specific for the unique topologies that are intrinsic to the linkage. Proteins can specifically bind to ubiquitin via ubiquitin-binding domains (UBDs). The distances between individual ubiquitin units in chains differ between lysine 63- and 48-linked chains.
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1999, 64, 4586-4589. From the cyclooctene figure below, it can be observed that one face is more exposed than the other, foreshadowing a discussion of privileged attack angles (see peripheral attack). 205px X-ray analysis of functionalized cyclooctanes provided proof of conformational preferences in these medium rings. Significantly, calculated models matched the obtained X-ray data, indicating that computational modeling of these systems could in some cases quite accurately predict conformations.
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AZD0530 is an inhibitor of Src and Abl family kinases1. It has been developed as treatment for malignancies because these kinases play a role in tumor invasion and proliferation. However, the Src family kinases (SFKs) are highly expressed in brain and have major effects on synaptic plasticity2. Moreover, the investigators have recently shown that a specific SFK, namely Fyn, is aberrantly activated by specific conformations of the Amyloid Beta (Aß) peptide from Alzheimer's disease (AD).
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These studies confirm that reactants that prefer s-trans conformations tend to undergo stepwise reaction. The degree of scrambling is also affected by carbene stability, migratory abilities, and nucleophilicity of solvent. The observation that the migratory ability of a substituent is inversely proportional to amount of carbene formed, indicates that under photolysis, there are competing pathways for many Wolff reactions. The only Wolff rearrangements that show no scrambling are s-cis constrained cyclic α-diazo ketones.
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NMR is also useful for investigating nonstandard geometries such as bent helices, non-Watson–Crick basepairing, and coaxial stacking. It has been especially useful in probing the structure of natural RNA oligonucleotides, which tend to adopt complex conformations such as stem-loops and pseudoknots. NMR is also useful for probing the binding of nucleic acid molecules to other molecules, such as proteins or drugs, by seeing which resonances are shifted upon binding of the other molecule.
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Stabilisation of the peptide upon the protein scaffold constrains the possible conformations which the peptide may take, thus increasing the binding affinity and specificity compared to libraries of free peptides. The Affimer protein scaffold was developed initially at the MRC Cancer Cell Unit in Cambridge then across two laboratories at the University of Leeds. Affimer technology has been commercialised and developed by Avacta Life Sciences, who are developing it as reagents for research and therapeutic applications.
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DEPDC1B is predicted to be predominantly alpha-helical. No significant beta- strands or beta structures exist with the protein. .BPS : A. W. Burgess and P. K. Ponnuswamy and H. A. Sheraga, Analysis of conformations of amino acid residues and prediction of backbone topography in proteins, Israel J. Chem., p239-286, 1974, vol12. D_R : G. Dele`age and B. Roux, An algorithm for secondary structure prediction based on class prediction, Protein Engineering, p289-294, 1987, vol 1, num 4.
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Differing from the normally conserved active site motif QACRG in other caspases, caspase-9 has the motif QACGG. When dimerized, caspase-9 has two different active site conformations within each dimer. One site closely resembles the catalytic site of other caspases, whereas the second has no 'activation loop', disrupting the catalytic machinery in that particular active site. Surface loops around the active site are short, giving rise to broad substrate specificity as the substrate-binding cleft is more open.
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Recently, SELEX has expanded to include the use of chemically modified nucleotides. These chemically modified oligonucleotides offer many potential advantages for selected aptamers including greater stability and nuclease resistance, enhanced binding for select targets, expanded physical properties - like increased hydrophobicity, and more diverse structural conformations. The genetic alphabet, and thus possible aptamers, is also expanded using unnatural base pairs the use of these unnatural base pairs was applied to SELEX and high affinity DNA aptamers were generated.
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NMR is also useful for investigating nonstandard geometries such as bent helices, non-Watson–Crick basepairing, and coaxial stacking. It has been especially useful in probing the structure of natural RNA oligonucleotides, which tend to adopt complex conformations such as stem- loops and pseudoknots. NMR is also useful for probing the binding of nucleic acid molecules to other molecules, such as proteins or drugs, by seeing which resonances are shifted upon binding of the other molecule.
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In other words, it achieves linear parallelization, leading to an approximately four orders of magnitude reduction in overall serial calculation time. A completed MSM may contain tens of thousands of sample states from the protein's phase space (all the conformations a protein can take on) and the transitions between them. The model illustrates folding events and pathways (i.e., routes) and researchers can later use kinetic clustering to view a coarse-grained representation of the otherwise highly detailed model.
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Stereoelectronic effects can have a significant influence in pharmaceutical research. Generally, the substitution of hydrogen by fluorine could be regarded as a way to tune both the hydrophobicity and the metabolic stability of a drug candidate. Moreover, it can have a profound influence on conformations, often due to stereoelectronic effects, in addition to normal steric effects resulting from the larger size of the fluorine atom. For instance, the ground state geometries of anisole (methoxybenzene) and (trifluoromethoxy)benzene differ dramatically.
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Globular proteins are proteins that contain a hydrophobic core and a hydrophilic surface. Globular proteins often assume a stable structure, unlike fibrous proteins, which have multiple conformations. The three-dimensional structure of globular proteins is typically easier to determine through X-ray crystallography and nuclear magnetic resonance than both fibrous proteins and membrane proteins, which makes globular proteins more attractive for protein design than the other types of proteins. Most successful protein designs have involved globular proteins.
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Alpha-sheet conformations have been observed in crystal structures of short non-natural peptides, especially those containing a mixture of L and D amino acids. The first crystal structure containing an alpha sheet was observed in the capped tripeptide Boc–AlaL–a-IleD–IleL–OMe.Di Blasio B, Saviano M, Fattorusso R, Lombardi A, Pedone C, Valle V, Lorenzi GP. (1994). A crystal structure with features of an antiparallel alpha-pleated sheet. Biopolymers 34(11):1463-8.
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He applied to the Colorado legislature for toll road charters for his roads and built the roads in conformations and at grades suitable for railways. His routes over Poncha Pass and Marshall Pass were purchased for road beds by the Denver and Rio Grande railway. Mears built several railroads during his 91 years, including the Rio Grande Southern Railroad from Durango to Ridgway, the Silverton Railroad, and the Silverton Northern Railroad. Several of his railroads were narrow gauge.
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Anatoly M Belostotskii (2015): "Conformer and conformation", chapter 2 of Conformational Concept For Synthetic Chemist's Use: Principles And In Lab Exploitation. 580 pages. .) Interactions with other molecules of the same or different compounds (for example, through hydrogen bonds) can significantly change the energy of conformations of a molecule. Therefore, the possible isomers of a compound in solution or in its liquid and solid phases many be very different from those of an isolated molecule in vacuum.
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The molecular demon switches mainly between two conformations. The first, or basic state, upon recognizing and binding the ligand or substrate following an induced fit, undergoes a change in conformation which leads to the second quasi-stable state: the protein-ligand complex. In order to reset the protein to its original, basic state, it needs ATP. When ATP is consumed or hydrolyzed, the ligand is released and the demon acquires again information reverting to its basic state.
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The amino acid sequence, , and the 3D molecular structure of crotamine have already been determined. The protein structure of crotamine could not be initially determined through protein crystallization nor X-ray diffraction. It was speculated that the difficulty was because crotamine has so many isoforms, leading to the formation of aggregates and different possible conformations of the protein. The structure and the shape of the protein was proposed through a 3D model generated by Siqueira et al.
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The internal angles of a flat regular hexagon are 120°, while the preferred angle between successive bonds in a carbon chain is about 109.5°, the tetrahedral angle. Therefore, the cyclohexane ring tends to assume certain non-planar (warped) conformations, which have all angles closer to 109.5° and therefore a lower strain energy than the flat hexagonal shape. The most important shapes are chair, half- chair, boat, and twist-boat. Their relative stabilities are: chair > twist boat > boat > half-chair.
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Structures of the significant conformations are shown: chair (1), half-chair (2), twist-boat (3) and boat (4). When ring flip happens completely from chair-to-chair, hydrogens that were previously axial (blue H in upper-left structure) turn equatorial and equatorial ones (red H in upper- left structure) turn axial. Each carbon bears one "up" and one "down" hydrogen. The C-H bonds in successive carbons are thus staggered so that there is little torsional strain.
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The difference in energy between conformations is called the A value and is well known for many different substituents. The A value is a thermodynamic parameter and was originally measured along with other methods using the Gibbs free energy equation and, for example, the Meerwein–Ponndorf–Verley reduction/Oppenauer oxidation equilibrium for the measurement of axial versus equatorial values of cyclohexanone/cyclohexanol (0.7 kcal mol−1).Eliel, E.L., Wilen, S.H., The Stereochemistry of Organic Compounds, Wiley-Interscience, 1994.
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Due to the cost of treating the electronic degrees of freedom, the computational cost of these simulations is far higher than classical molecular dynamics. This implies that AIMD is limited to smaller systems and shorter times. Ab initio quantum mechanical and chemical methods may be used to calculate the potential energy of a system on the fly, as needed for conformations in a trajectory. This calculation is usually made in the close neighborhood of the reaction coordinate.
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Correspondingly, three different conformations classified as the opened, closed and occluded states are assigned to Met20. In addition, an extra distorted conformation of Met20 was defined due to its indistinct characterization results. The Met20 loop is observed in its occluded conformation in the three product ligating intermediates, where the nicotinamide ring is occluded from the active site. This conformational feature accounts for the fact that the substitution of NADP+ by NADPH is prior to product dissociation.
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Helmchen's Postulates are the theoretical models used to predict the elution order and extent of separation of diastereomers (including those formed from CDAs) that are adsorbed onto a surface. Although Helmchen’s postulates are specific for amides on silica gel using liquid chromatography, the postulates provide fundamental guidelines for other molecules. Helmchen’s Postulates are: #Conformations are the same is a in solution and when adsorbed. #Diastereomers bind to surfaces (silica gel in normal phase chromatography) mainly with hydrogen bonding.
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The leucine 41 has a non-polar side chain that allows for transient penetration of the water molecules. This increases the polarity of the redox site environment. The Leucine 41 side chain has two different conformations; reduced and the oxidized form. The conformation in the reduced form is open and allows water molecules near the [Fe(S-Cys)4] 2+ active site and stabilizing the higher net positive charge of the reduced Fe 2+ oxidation state.
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As an input LiSiCA requires at least one reference compound and database of target compounds. For 3D screening this database has to be a pregenerated database of conformations of target and for 2D screening a topology, that is, a list of atoms and bonds, for each target compound. On each step the algorithm compares reference compound to one of the compounds from target compounds based on their 2D or 3D representation. Both compounds(molecules) are converted to molecular graphs.
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Sivilotti uses electrophysiological methods to assess receptor function, combined with molecular biology methods to alter receptor structure. In addition she collaborates with crystallographers and molecular dynamicists to complement the functional work. [1] Her lab specialises in recording single ion channel activity and analysing it by the fitting of activation mechanisms. Mechanisms specify the number of conformations in which the channel-receptor protein can exist, the number of ligand molecules bound, and the connections between the states.
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Prions are proteins of particular amino acid sequences in particular conformations. They propagate themselves in host cells by making conformational changes in other molecules of protein with the same amino acid sequence, but with a different conformation that is functionally important or detrimental to the organism. Once the protein has been transconformed to the prion folding it changes function. In turn it can convey information into new cells and reconfigure more functional molecules of that sequence into the alternate prion form.
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NS5A is a large hydrophilic phosphoprotein that is essential for the HCV life cycle and is found in association with virus-induced membrane vesicles, termed the membranous web. NS5A is a proline-rich protein composed of approximately 447 amino acids, which is divided into three domains. These domains are linked by two low- complexity sequences that are either serine- or proline-rich. Domain I is a zinc binding domain and X-ray crystallography studies indicated alternative dimer conformations of domain I of NS5A.
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Simply put, the migration of the non-bridgehead carbon provides for the least amount of total atom movement, something that plays into the energetics of the reaction. This least movement consideration would prove important in the TDR mechanism as it accounts for products with intermediates passing through unfavorable conformations. However, McKinney and Patel also confirm that traditional factors such as developing positive charge stability still play a crucial role in the direction of expansion. They accomplish this by expanding 2-norbornenyl carbinyl systems.
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The larger affinity of the ligand for the R state means that the latter is preferentially stabilized by the binding. The Monod-Wyman-Changeux (MWC) model for concerted allosteric transitions went a step further by exploring cooperativity based on thermodynamics and three-dimensional conformations. It was originally formulated for oligomeric proteins with symmetrically arranged, identical subunits, each of which has one ligand binding site. According to this framework, two (or more) interconvertible conformational states of an allosteric protein coexist in a thermal equilibrium.
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The structure of several hemolysins has been solved by X-ray crystallography in the soluble and pore-forming conformations. For example, α-hemolysin of Staphylococcus aureus forms a homo- heptameric β-barrel in biological membranes. The Vibrio cholerae cytolysin; also forms a heptameric pore, however Staphylococcus aureus γ-hemolysin; forms a pore that is octameric. The heptamer of α-hemolysin from Staphylococcus aureus has a mushroom-like shape and measures up to 100 Å in diameter and 100 Å in height.
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The Levinthal paradox states that if an averaged sized protein would sample all possible conformations before finding the one with the lowest energy, the whole process would take billions of years. Proteins typically fold within 0.1 and 1000 seconds. Therefore, the protein folding process must be directed some way through a specific folding pathway. The forces that direct this search are likely to be a combination of local and global influences whose effects are felt at various stages of the reaction.
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The rate equations of Gutowsky, McCall, and Slichter (1951) were used by Gutowsky and Saika to investigate proton exchange in aqueous electrolyte solutions. They were able to apply the theory to more than two sites and calculate the predicted collapse of the multiplet structure as the rate of exchange increased. However, they were unable to present cases in which the actual collapse was observable. Gutowsky and Charles H. Holm studied intramolecular rotational rates of amides, establishing that energy barriers existed between molecular conformations.
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Two known binding sites for VMAT inhibitors include the Reserpine (RES) binding site and the Tetrabenazine (TBZ) binding site. Some evidence suggests these two sites may overlap or may actually exist as two separate conformations of the same binding site. VMAT inhibitors tend to fall into two classes; those that interact with the RES binding site and those that interact with the TBZ binding site. Reserpine (RES), Methoxytetrabenazine (MTBZ), and the drug Amiodarone bind to the RES binding site conformation.
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Acetic anhydride in a glass bottle Acetic anhydride, like most acid anhydrides, is a flexible molecule with a nonplanar structure. The pi system linkage through the central oxygen offers very weak resonance stabilization compared to the dipole-dipole repulsion between the two carbonyl oxygens. The energy barriers to bond rotation between each of the optimal aplanar conformations are quite low. Like most acid anhydrides, the carbonyl carbon atom of acetic anhydride has electrophilic character, as the leaving group is carboxylate.
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The dual repeat BRCT domain of the BRCA1 protein is an elongated structure approximately 70 Å long and 30–35 Å wide. The 85–95 amino acid domains in BRCT can be found as single modules or as multiple tandem repeats containing two domains. Both of these possibilities can occur in a single protein in a variety of different conformations. The C-terminal BRCT region of the BRCA1 protein is essential for repair of DNA, transcription regulation and tumor suppressor function.
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A major application of supramolecular chemistry is the design and understanding of catalysts and catalysis. Non-covalent interactions are extremely important in catalysis, binding reactants into conformations suitable for reaction and lowering the transition state energy of reaction. Template-directed synthesis is a special case of supramolecular catalysis. Encapsulation systems such as micelles, dendrimers, and cavitands are also used in catalysis to create microenvironments suitable for reactions (or steps in reactions) to progress that is not possible to use on a macroscopic scale.
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To simplify this space, protein design methods use rotamer libraries that assume ideal values for bond lengths and bond angles, while restricting χ dihedral angles to a few oft- observed low-energy conformations termed rotamers. Rotamer libraries describe rotamers based on an analysis of many protein structures. Backbone-independent rotamer libraries describe all rotamers. Backbone-dependent rotamer libraries, in contrast, describe the rotamers as how likely they are to appear depending on the protein backbone arrangement around the side chain.
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The effects of neighboring bases and secondary structure to detect the frequency of frameshift mutations has been investigated in depth using fluorescence. Fluorescently tagged DNA, by means of base analogues, permits one to study the local changes of a DNA sequence. Studies on the effects of the length of the primer strand reveal that an equilibrium mixture of four hybridization conformations was observed when template bases looped-out as a bulge, i.e. a structure flanked on both sides by duplex DNA.
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Many of these atoms are directly moulded into the template, and fit together by pushing plastic stubs into small holes. The plastic grips well and makes bonds difficult to rotate, so that arbitrary torsion angles can be set and retain their value. The conformations of the backbone and side chains are determined by pre-computing the torsion angles and then adjusting the model with a protractor. The plastic is white and can be painted to distinguish between O and N atoms.
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The double helix makes one complete turn about its axis every 10.4–10.5 base pairs in solution. This frequency of twist (known as the helical pitch) depends largely on stacking forces that each base exerts on its neighbours in the chain. Double-helical RNA adopts a conformation similar to the A-form structure. Other conformations are possible; in fact, only the letters F, Q, U, V, and Y are now available to describe any new DNA structure that may appear in the future.
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Conformations of five-membered rings are limited to two, envelope and twist. The envelope conformation has four atoms in a plane while the twist form only has three. In the envelope form two different scenarios can be envisioned; one where the ring oxygen is in the four atom plane and one where it is puckered above or below the plane. When the ring oxygen is not in the plane the substituents eclipse and when it is in the plane torsional strain is relieved.
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SmFRET can also be used to study the conformations of molecules freely diffusing in a liquid sample. In freely-diffusing smFRET experiments (or diffusion-based smFRET), the same biomolecules are free to diffuse in solution while being excited by a small excitation volume (usually a diffraction-limited spot). Bursts of photons due a single-molecule crossing the excitation spot are acquired with SPAD detectors. The confocal spot is usually fixed in a given position (no scanning happens, and no image is acquired).
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ENDOR- Induced EPR (EI-EPR) displays ENDOR transitions as a function of the magnetic field. While the magnetic field is swept through the EPR spectrum, the frequency follows the Zeeman frequency of the nucleus. The EI-EPR spectra can be collected in two ways: (1) difference spectra/ (2) frequency modulated rf field without Zeeman modulation. This technique was established by Hyde and is especially useful for separating overlapping EPR signals which result from different radicals, molecular conformations or magnetic sites.
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His death in 1893 at the age of 31 meant his ideas sank into obscurity. It was only in 1918 when , based on the molecular structure of diamond that had recently been solved using the then very new technique of X-ray crystallography, was able to successfully argue that Sachse's chair was the pivotal motif.This history is nicely summarized here: . Derek Barton and Odd Hassel shared the 1969 Nobel Prize for work on the conformations of cyclohexane and various other molecules.
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Dimer formation of the two ABC domains of transporters requires ATP binding. It is generally observed that the ATP bound state is associated with the most extensive interface between ABC domains, whereas the structures of nucleotide-free transporters exhibit conformations with greater separations between the ABC domains. Structures of the ATP-bound state of isolated NBDs have been reported for importers including HisP, GlcV, MJ1267, E. coli MalK (E.c.MalK), T. litoralis MalK (TlMalK), and exporters such as TAP, HlyB, MJ0796, Sav1866, and MsbA.
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The structure of Sl6 family transporters share 20-25% sequence similarity with LeuTA providing an evolutionary relationship between the transporter and the leucine transporter protein. Because of the similarity, the LeuTa protein provides a very close template model for the studying the transporters in greater detail. The GABA transporter exists in two different conformations. The transporters have general structure of 12 alpha helices with both end - N Terminus and C-terminus in the cytoplasm with glycosylation sequence in the transmembrane helices.
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The structural formula and the bond angles are not usually sufficient to completely describe the geometry of a molecule. There is a further degree of freedom for each carbon–carbon bond: the torsion angle between the atoms or groups bound to the atoms at each end of the bond. The spatial arrangement described by the torsion angles of the molecule is known as its conformation. Newman projections of the two conformations of ethane: eclipsed on the left, staggered on the right.
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The A-value for a methyl group is 1.74 as derived from the chemical equilibrium above. This means it costs of energy to have a methyl group in the axial position compared to the equatorial position. A-Values are numerical values used in the determination of the most stable orientation of atoms in a molecule (conformational analysis), as well as a general representation of steric bulk. A-values are derived from energy measurements of the different cyclohexane conformations of a monosubstituted cyclohexane chemical.
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A random coil is a polymer conformation where the monomer subunits are oriented randomly while still being bonded to adjacent units. It is not one specific shape, but a statistical distribution of shapes for all the chains in a population of macromolecules. The conformation's name is derived from the idea that, in the absence of specific, stabilizing interactions, a polymer backbone will "sample" all possible conformations randomly. Many linear, unbranched homopolymers — in solution, or above their melting temperatures — assume (approximate) random coils.
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Crystal structures of the Escherichia coli MscS in the open and closed conformations are available. E. coli MscS folds as a homoheptamer with a cylindrical shape, and can be divided into transmembrane and extramembrane regions: an N-terminal periplasmic region, a transmembrane region, and a C-terminal cytoplasmic region (middle and C-terminal domains). The transmembrane region forms a channel through the membrane that opens into a chamber enclosed by the extramembrane portion, the latter connecting to the cytoplasm through distinct portals.
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X-ray crystallography is the primary method for determining the molecular conformations of biological macromolecules, particularly protein and nucleic acids such as DNA and RNA. In fact, the double-helical structure of DNA was deduced from crystallographic data. The first crystal structure of a macromolecule was solved in 1958, a three-dimensional model of the myoglobin molecule obtained by X-ray analysis. The Protein Data Bank (PDB) is a freely accessible repository for the structures of proteins and other biological macromolecules.
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DNA topology is the tertiary conformations of DNA, such as supercoiling, knotting, and catenation. Topology of DNA can be disrupted by most metabolic processes: RNA polymerase can cause positive supercoils by over-winding the DNA in front of the enzyme, and can also cause negative supercoils by under-winding the DNA behind the enzyme. DNA polymerase has the same effect in DNA replication. Positive and negative supercoiling balance out the entire global topology of the DNA, so overall, the topology remains the same.
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"Targeting renal dipeptidase (dehydropeptidase I) for inactivation by mechanism-based inactivators." Journal of Medicinal Chemistry 34.6 (1991): 1914-916. Web. The addition of cobalt or manganese ions cause the enzyme to take on different conformations, which suggests that the enzyme may be able to hydrolyze different dipeptides depending on which metal ions are present—aka the metal-content of one’s micronutrient intake could affect their renal dipeptidase’s ability to metabolize various dipeptides.Hayman, Selma, Joselina S. Gatmaitan, and Elizabeth K. Patterson.
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The most energetically unfavorable interaction involves axial substitution at the vertex of the boat portion of the ring (6.1 kcal/mol). 600px These energetic differences can help rationalize the lowest energy conformations of 8 atom ring structures containing an sp2 center. In these structures, the chair-boat is the ground state model, with substitution forcing the structure to adopt a conformation such that non-bonded interactions are minimized from the parent structure.Pawar, D.M.; Moody, E.M.; Noe, E.A. J. Org. Chem.
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For almost 50 years molecular biology was based on two dogmas: (i) equating biological function of the protein with a unique three-dimensional structure and (ii) assuming exquisite specificity in protein complexes. Specificity/selectivity is ensured by unambiguous set of interactions formed between the protein and its ligand (another protein, DNA, RNA or small molecule). Many protein complexes however, contain functionally important/critical regions, which remain highly dynamic in the complex or adopt different conformations. This phenomenon is defined fuzziness.
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PDE5 is an enzyme that accepts cGMP and breaks it down. Sildenafil, vardenafil and tadalafil are inhibitors of this enzyme, which bind to the catalytic site of PDE5. Both inhibitors bind with high affinity and specificity, and cGMP-binding to the allosteric sites stimulates binding of PDE5 inhibitors at the catalytic site. The kinetics of inhibitor binding and inhibition of catalysis imply the existence of two PDE5 conformers, and results of native gel electrophoresis reveal that PDE5 exists in two apparently distinct conformations, i.e.
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2 shows a representation of a four-carbon isoprene backbone unit with an extra carbon atom at each end to indicate its connections to adjacent units on a chain. It has three single C-C bonds and one double bond. It is principally by rotating about the C-C single bonds that a polyisoprene chain randomly explores its possible conformations. Sections of chain containing between two and three isoprene units have sufficient flexibility that they may be considered statistically de-correlated from one another.
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Invoking the theory of rubber elasticity, one considers a polymer chain in a cross-linked network as an entropic spring. When the chain is stretched, the entropy is reduced by a large margin because there are fewer conformations available. Therefore, there is a restoring force, which causes the polymer chain to return to its equilibrium or unstretched state, such as a high entropy random coil configuration, once the external force is removed. This is the reason why rubber bands return to their original state.
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Rigid blocks are defined as blocks where all inter residue distances are conserved across conformations. The method RIBFIND developed by Pandurangan and Topf identifies rigid bodies in protein structures by performing spacial clustering of secondary structural elements in proteins. The RIBFIND rigid bodies have been used to flexibly fit protein structures into cryo electron microscopy density maps. A general method to identify dynamical domains, that is protein regions that behave approximately as rigid units in the course of structural fluctuations, has been introduced by Potestio et al.
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However, several structural details set ALDOC apart. For instance, the Arg303 residue in ALDOC adopts an intermediate conformation between the liganded and unliganded structures observed in the other isozymes. Also, the C-terminal region between Glu332 and Lys71 forms a salt bridge with the barrel region that is absent in the A and B isoforms. Moreover, the electrostatic surface of ALDOC is more negatively charged, which may serve as an acidic binding site or as a docking site to accommodate the C-terminal conformations.
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The ligand binding site, known as AF2 domain , is expressed by exons 4-8, corresponding to 253 amino acids, and its structure is of great interest to SPRM development. It consists of 10 α-helices (H1, H3-H12) forming 3 layered bundle entwined with 4 β-sheets . H12 is a condensed contiguous unit composed of helices 10 and 11, which has been suggested to participate in the process of co-activator binding. The ligand binding domain of the receptor is in equilibrium between two different conformations.
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The crystal structure of PRC1 has only recently been characterized in vitro. In 2013, PRC1 was illustrated as a lengthy molecule consisting of a C-terminal spectrin microtubule-binding domain, an extended rod domain, and an N-terminal dimerization domain. Consisting of an intricate arrangement of α-helices, the rod domain, together with the dimerization- conducting N terminus cooperate to facilitate binding of other proteins, such as Kinesin-4, to PRC1. PRC1’s rod domain adopts multiple conformations, all affected by its C-terminal spectrin domain.
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The resulting adduct decarboxylates. The resulting 1,3-dipole reductively acetylates lipoamide-E2. In terms of details, biochemical and structural data for E1 revealed a mechanism of activation of TPP coenzyme by forming the conserved hydrogen bond with glutamate residue (Glu59 in human E1) and by imposing a V-conformation that brings the N4’ atom of the aminopyrimidine to intramolecular hydrogen bonding with the thiazolium C2 atom. This unique combination of contacts and conformations of TPP leads to formation of the reactive C2-carbanion, eventually.
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The first single-molecule experiments were patch clamp experiments performed in the 1970s, but these were limited to studying ion channels. Today, systems investigated using single-molecule techniques include the movement of myosin on actin filaments in muscle tissue and the spectroscopic details of individual local environments in solids. Biological polymers' conformations have been measured using atomic force microscopy (AFM). Using force spectroscopy, single molecules (or pairs of interacting molecules), usually polymers, can be mechanically stretched and their elastic response recorded in real time.
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However, caution should be used in using the results as evidence for shared evolutionary ancestry because of the possible confounding effects of convergent evolution by which multiple unrelated amino acid sequences converge on a common tertiary structure. Structural alignments can compare two sequences or multiple sequences. Because these alignments rely on information about all the query sequences' three-dimensional conformations, the method can only be used on sequences where these structures are known. These are usually found by X-ray crystallography or NMR spectroscopy.
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The Nuclear Ensemble Approach (NEA) is a general method for simulations of diverse types of molecular spectra. It works by sampling an ensemble of molecular conformations (nuclear geometries) in the source state, computing the transition probabilities to the target states for each of these geometries, and performing a sum over all these transitions convoluted with shape function. The result is an incoherent spectrum containing absolute band shapes through inhomogeneous broadening. NEA simulates the spectrum in three steps: firstly an ensemble of molecular geometries is generated.
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Finding related conformations in the Protein Data Bank (PDB) is essential in many areas of bioinformatics. To assist this task, a search engine that uses a compact database to quickly identify protein segments obeying a set of primary, secondary and tertiary structure constraints was designed. The database contains information such as amino acid sequence, secondary structure, disulfide bonds, hydrogen bonds, and atoms in contact as calculated from all protein structures in the PDB. The search engine parses the database and returns hits that match the queried parameters.
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Secondary structure prediction is a set of techniques in bioinformatics that aim to predict the local secondary structures of proteins based only on knowledge of their amino acid sequence. For proteins, a prediction consists of assigning regions of the amino acid sequence as likely alpha helices, beta strands (often noted as "extended" conformations), or turns. The success of a prediction is determined by comparing it to the results of the DSSP algorithm (or similar e.g. STRIDE) applied to the crystal structure of the protein.
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Some versions are based on very carefully curated data and are used primarily for structure validation, while others emphasize relative frequencies in much larger data sets and are the form used primarily for structure prediction, such as the Dunbrack rotamer libraries. Side-chain packing methods are most useful for analyzing the protein's hydrophobic core, where side chains are more closely packed; they have more difficulty addressing the looser constraints and higher flexibility of surface residues, which often occupy multiple rotamer conformations rather than just one.
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Popular methods to control temperature include velocity rescaling, the Nosé–Hoover thermostat, Nosé–Hoover chains, the Berendsen thermostat, the Andersen thermostat and Langevin dynamics. The Berendsen thermostat might introduce the flying ice cube effect, which leads to unphysical translations and rotations of the simulated system. It is not trivial to obtain a canonical ensemble distribution of conformations and velocities using these algorithms. How this depends on system size, thermostat choice, thermostat parameters, time step and integrator is the subject of many articles in the field.
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Jucker’s research has focused on understanding how certain proteins cause disease by adopting abnormal 3-dimensional shapes (conformations) in the nervous system. In collaboration with Lary Walker at Emory University, Jucker was the first to show in experimental mice that the accumulation of abnormally folded proteins in Alzheimer’s disease occurs by a prion-like mechanism. The prion concept has since been expanded to include several other proteins, including tau and α-synuclein, which similarly misfold and aggregate in a class of diseases known as proteopathies.
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The primary function of alpha-actinin 2 is to crosslink filamentous actin molecules and titin molecules from adjoining sarcomeres at Z-discs, a function that is modulated by phospholipids. It is clear from studies by Hampton et al. that this crosslinking can assume a variety of conformations, with preferences for 60° and 120° angles. Alpha- actinin 2 also functions in docking signalling molecules at Z-discs, and additional studies have also implicated alpha-actinin 2 in the binding of cardiac ion channels, Kv1.5 in particular.
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All members of the chymotrypsin family of serine proteases have very similar structures. In all cases, including factor D, there are two antiparallel β-barrel domains with each barrel containing six β-strands with the same typology in all enzymes. The major difference in backbone structure between Factor D and the other serine proteases of the chymotrpsin family is in the surface loops connecting the secondary structural elements. Factor D displays different conformations of major catalytic and substrate-binding residues typically found in the chrotrypsin family.
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Printing materials must fit a broad spectrum of criteria, one of the foremost being biocompatibility. The resulting scaffolds formed by 3D printed materials should be physically and chemically appropriate for cell proliferation. Biodegradability is another important factor, and insures that the artificially formed structure can be broken down upon successful transplantation, to be replaced by a completely natural cellular structure. Due to the nature of 3D printing, materials used must be customizable and adaptable, being suited to wide array of cell types and structural conformations.
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Three representative conformations of the benzene dimer In chemistry, pi stacking (also called π–π stacking) refers to attractive, noncovalent interactions between aromatic rings, since they contain pi bonds. These interactions are important in nucleobase stacking within DNA and RNA molecules, protein folding, template-directed synthesis, materials science, and molecular recognition, although some research suggests that pi stacking may not be operative in some of these applications. Despite intense experimental and theoretical interest, there is no unified description of the factors that contribute to pi stacking interactions.
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The preferred geometries of the benzene dimer have been modeled at a high level of theory with MP2-R12/A computations and very large counterpoise-corrected aug-cc-PVTZ basis sets. The two most stable conformations are the parallel displaced and T-shaped, which are essentially isoenergetic. In contrast, the sandwich configuration maximizes overlap of the pi system, which destabilizes the interaction. The sandwich configuration represents an energetic saddle point, which is consistent with the relative rarity of this configuration in x-ray crystal data.
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The two-state model of receptor activation has given way to multistate models with intermediate conformational states. The discovery of functional selectivity and that ligand-specific receptor conformations occur and can affect interaction of receptors with different second messenger systems may mean that drugs can be designed to activate some of the downstream functions of a receptor but not others. This means efficacy may actually depend on where that receptor is expressed, altering the view that efficacy at a receptor is receptor-independent property of a drug.
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The macromolecules which the PZP has been shown to bind include those associated with pregnancy, such as the placenta growth factor, glycodelin, and the vascular endothelial growth factor. It has been stated that more compact, transformed conformations of PZP occur as a result of thioester bond cleavage of the PZP resulting from interaction with small amine molecules or proteases. The mechanisms of how these transformed PZPs, complexed with proteases, act as ligands for LRP are still enigmatic. It has been demonstrated that PZP has plasmin-binding capabilities.
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The figure below shows the energetic penalty between placing the methyl group at certain sites within the boat-chair-boat structure. Unlike canonical small ring systems, the cyclodecane system with the methyl group placed at the "corners" of the structure exhibits no preference for axial vs. equatorial positioning due to the presence of an unavoidable gauche-butane interaction in both conformations. Significantly more intense interactions develop when the methyl group is placed in the axial position at other sites in the boat-chair- boat conformation.
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In addition bird mounds sometimes appear in different conformations where the wings of the bird may be folded or unfolded to different degrees, suggesting various postures in flying. There are some instances where these different poses may suggest a freeze frame view of a bird flying - wings outstretched, wings partially folded, and wings outstretched again. Hochunk ancestors naturally buried their dead next to lakes and rivers, and on hillsides. These locations would later become valued as some of the best places to live by settlers.
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Uhlenbeck was first published in 1968 at Harvard University for an article titled, “Some Effects on Noncomplementary Bases on the Stability of Helical Complexes of Polyribonucleotides.” The study overviews the conformation of specific polyribonucleotide sequences. The group used synthetic polyribonucleotides with slight distortions and studied whether their conformations stayed in the helical formation or if they took on a new formation. They determined that some of the instability in formation could be due to the non-complementary bases or the bases directly next to those that are non-complementary.
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Experimental configurations used to study free surface flows. From left: liquid bridge, dripping, jetting Capillary thinning and breakup of complex fluids can be studied using different configurations. Historically, mainly three types of free-surface conformations have been employed in experiments: statically-unstable liquid bridges, dripping from a nozzle under gravity and continuous jets. Even though the initial evolution of the capillary instability is affected by the type of conformation used, each configurations capture the same phenomenon at the last stages close to breakup, where thinning dynamics is dominated by fluid properties exclusively.
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The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the Cu(I) bound, Cu(II) bound, and unbound conformations, which differ by only small changes in orientation. The extracellular E2 domain, a dimeric coiled coil and one of the most highly conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans.
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This double structural constraint decreases the diversity of the conformations that the variable regions can adopt, and this reduction in conformational diversity lowers the entropic cost of molecular binding when interaction with the target causes the variable regions to adopt a single conformation. As a consequence, peptide aptamers can bind their targets tightly, with binding affinities comparable to those shown by antibodies (nanomolar range). Peptide aptamer scaffolds are typically small, ordered, soluble proteins. The first scaffold, which is still widely used, is Escherichia coli thioredoxin, the trxA gene product (TrxA).
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A unique feature of DewA is its capacity to exist as two types of conformers in solution, both able to form rodlet assemblies but at different rates. Despite these differences in structural and self-assembly mechanisms, both EAS and DewA form robust fibrillar monolayers, meaning that there must exist several pathways, protein sequences and tertiary conformations able to self-assemble into amphipathic monolayers. Further characterisation of both EAS and DewA and their rodlet self-assembly mechanisms will open up opportunities for rational design of hydrophobins with novel biotechnological applications.
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Identifying the secondary structure is helpful in further analyzing the function of this protein. Alpha helices are the strongest indicators of transmembrane regions, as the helical structure can satisfy all backbone hydrogen-bonds internally. This is why the secondary structure of this protein is practical, as many of the alpha helices lie in the predicted transmembrane regions. Other key structures identified in this protein include extended strands, which are hypothesized to be important folding regions, and random coils, a class of conformations in the absence of a regular secondary structure.
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These five structures exist in equilibrium and interconvert, and the interconversion is much more rapid with acid catalysis. Widely proposed arrow-pushing mechanism for acid-catalyzed dynamic equilibrium between the α- and β- anomers of D-glucopyranose The other open-chain isomer -glucose similarly gives rise to four distinct cyclic forms of -glucose, each the mirror image of the corresponding -glucose. The rings are not planar, but are twisted in three dimensions. The glucopyranose ring (α or β) can assume several non-planar shapes, analogous to the "chair" and "boat" conformations of cyclohexane.
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Similarly, the glucofuranose ring may assume several shapes, analogous to the "envelope" conformations of cyclopentane. In the solid state, only the glucopyranose forms are observed, forming colorless crystalline solids that are highly soluble in water and acetic acid but poorly soluble in methanol and ethanol. They melt at (α) and (β), and decompose starting at 188 °C with release of various volatile products, ultimately leaving a residue of carbon.Wenyue Kang and Zhijun Zhang (2020): "Selective Production of Acetic Acid via Catalytic Fast Pyrolysis of Hexoses over Potassium Salts", Catalysts, volume 10, pages 502-515.
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All the early work was based on mechanisms that were essentially generalisations of the simple scheme proposed by del Castillo & Katz in 1957, in which the receptor existed in only two conformations, open and shut. It was only when the glycine receptor was investigated that it was realised that it was possible to detect an intermediate shut state (dubbed the "flipped" conformation), between the resting conformation and the open state. Subsequently, it was discovered that this extra "flipped" conformation was detectable too in the nicotinic acetylcholine receptor. Lape et al.
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Its C-terminal part contains many serine-rich repeats. Using gamma ray examination, it was determined that sericin fibers are composed typically of three layers, all with fibers running in different patterns of directionality. The innermost layer, typically is composed of longitudinally running fibers, the middle layer is composed of cross fiber directional patterned fibers, and the outer layer consists of fiber directional fibers. The overall structure can also vary based on temperature, whereas the lower the temperature, there were typically more β-sheet conformations than random amorphous coils.
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CaMKII gamma holoenzyme in its (A) closed and the (B) open conformations /calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase that is regulated by the /calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediator of learning and memory. CaMKII is also necessary for homeostasis and reuptake in cardiomyocytes, chloride transport in epithelia, positive T-cell selection, and CD8 T-cell activation. Misregulation of CaMKII is linked to Alzheimer’s disease, Angelman syndrome, and heart arrhythmia.
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These arms may adopt one of several conformations depending on buffer salt concentrations and the sequence of nucleobases closest to the junction. The structure is named after Robin Holliday, the molecular biologist who proposed its existence in 1964. In biology, Holliday junctions are a key intermediate in many types of genetic recombination, as well as in double- strand break repair. These junctions usually have a symmetrical sequence and are thus mobile, meaning that the four individual arms may slide through the junction in a specific pattern that largely preserves base pairing.
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Early on, it has been argued that some proteins, especially those consisting of many subunits, could be regulated by a generalized MWC mechanism, in which the transition between R and T state is not necessarily synchronized across the entire protein. In 1969, Wyman proposed such a model with "mixed conformations" (i.e. some protomers in the R state, some in the T state) for respiratory proteins in invertebrates. Following a similar idea, the conformational spread model by Duke and colleagues subsumes both the KNF and the MWC model as special cases.
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EVI5L contains a RAB-GAP TBC domain, which is involved with regulating membrane trafficking by cycling between inactive (GDP-bound) and active (GTP- bound) conformations. It also has the apolipophorin-III and tetratricopeptide repeat (TPR) domains. Apolipophorin-III play vital roles in the transport of lipids and lipoprotein metabolism,National Center for Biotechnology Information: Conserved Domains Database (CDD) and Resource Group Conserved domains for EVI5L ecotropic viral integration site 5-like (Homo sapiens) while TPR mediates protein-protein interactions and the assembly of multi protein complexes. These three domains are highly conserved in EVI5L orthologs.
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The oligostilbenes amurensin A, B, C, D, E, F,Four Novel Oligostilbenes from the Roots of Vitis amurensis. Kai-Sheng Huang, Mao Lin, Lin-Ning Yu and Man Kong, Tetrahedron, 3 March 2000, Volume 56, Issue 10, Pages 1321–1329, G, H, I, J, K, L and MAnti-inflammatory tetramers of resveratrol from the roots of Vitis amurensis and the conformations of the seven-membered ring in some oligostilbenes. Kai-Sheng Huang, Mao Lin, and Gui- Fang Cheng, Phytochemistry, September 2001, Volume 58, Issue 2, Pages 357–362, can be found in V. amurensis.
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Dark proteins are not applicable to the structure-function paradigm the all proteins follow. They are predominately consisted of Intrinsically Disordered Proteins (IDP) that are necessary for certain biological function such as splicing, transcriptional and post-translational signaling, and signaling via protein networks. These processes are commonly executed intracellularly, however, dark proteins are over-represented in the extra-cellular matrix and on the endoplasmic reticulum. Dark proteins behave similarly to polymers and are capable of taking on many if not infinite conformations form due to the adaptability of the polypeptide chain.
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The active chaperonin role is in turn involved with specific chaperonin–substrate interactions that may be coupled to conformational rearrangements of the chaperonin. Probably the most popular model of the chaperonin active role is the iterative annealing mechanism (IAM), which focus on the effect of iterative, and hydrophobic in nature, binding of the protein substrate to the chaperonin. According to computational simulation studies, the IAM leads to more productive folding by unfolding the substrate from misfolded conformations or by prevention from protein misfolding through changing the folding pathway.
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The cloroindole part interacted with the hydrophobic core of the pocket and influenced the binding mode of the R120393 so it went deeper into the pocket compared to the wing I position of other DATA analogs. Crystal structures showed that the DATA compounds could bind the NNIBP in different conformations. The capability to bind in multiple modes made the NNRTIs stronger against drug-resistance mutations. Variability between the inhibitors could be seen when the chemical composition, size of wing I and the two linker groups connecting the rings were altered.
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Molecular mechanics force-fields, which have been used mostly in molecular dynamics simulations, are optimized for the simulation of single sequences, but protein design searches through many conformations of many sequences. Thus, molecular mechanics force-fields must be tailored for protein design. In practice, protein design energy functions often incorporate both statistical terms and physics-based terms. For example, the Rosetta energy function, one of the most-used energy functions, incorporates physics- based energy terms originating in the CHARMM energy function, and statistical energy terms, such as rotamer probability and knowledge-based electrostatics.
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This animation illustrates the complexity of a protein design search, which typically compares all the rotamer-conformations from all possible mutations at all residues. In this example, the residues Phe36 and His 106 are allowed to mutate to, respectively, the amino acids Tyr and Asn. Phe and Tyr have 4 rotamers each in the rotamer library, while Asn and His have 7 and 8 rotamers, respectively, in the rotamer library (from the Richardson's penultimate rotamer library). The animation loops through all (4 + 4) x (7 + 8) = 120 possibilities.
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In statistical mechanics, configuration entropy is the portion of a system's entropy that is related to discrete representative positions of its constituent particles. For example, it may refer to the number of ways that atoms or molecules pack together in a mixture, alloy or glass, the number of conformations of a molecule, or the number of spin configurations in a magnet. The name might suggest that it relates to all possible configurations or particle positions of a system, excluding the entropy of their velocity or momentum, but that usage rarely occurs.
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A Ramachandran plot can be used in two somewhat different ways. One is to show in theory which values, or conformations, of the ψ and φ angles are possible for an amino-acid residue in a protein (as at top right). A second is to show the empirical distribution of datapoints observed in a single structure (as at right, here) in usage for structure validation, or else in a database of many structures (as in the lower 3 plots at left). Either case is usually shown against outlines for the theoretically favored regions.
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As conformations began to grow, both parties became more biased, with media owners down to reporters feeling threatened with Chávez even calling out individual journalists by name in speeches. By January 2002, Chávez supporters were attacking independent reporters, with the headquarters of El Universal assaulted by hundreds of Chavistas, Globovision reporters attacked while they were attempting to record Aló Presidente and a bomb attack on newspaper Así Es la Noticia. As a result of being "besieged" by Chávez, the media lost its perspective and began to increase its political involvement assisting the opposition.
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The RCL forms the initial interaction with the target protease in inhibitory molecules. Structures have been solved showing the RCL either fully exposed or partially inserted into the A-sheet, and serpins are thought to be in dynamic equilibrium between these two states. The RCL also only makes temporary interactions with the rest of the structure, and is therefore highly flexible and exposed to the solvent. The serpin structures that have been determined cover several different conformations, which has been necessary for the understanding of their multiple-step mechanism of action.
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Silent mutations affect protein folding and function. Normally a misfolded protein can be refolded with the help of molecular chaperones. RNA typically produces two common misfolded proteins by tending to fold together and become stuck in different conformations and it has a difficulty singling in on the favored specific tertiary structure because of other competing structures. RNA-binding proteins can assist RNA folding problems, however, when a silent mutation occurs in the mRNA chain, these chaperones do not bind properly to the molecule and are unable to redirect the mRNA into the correct fold.
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HMG-box containing proteins only bind non-B-type DNA conformations (kinked or unwound) with high affinity. HMG-box domains are found in high mobility group proteins, which are involved in the regulation of DNA-dependent processes such as transcription, replication, and DNA repair, all of which require changing the conformation of chromatin. The single and the double box HMG proteins alter DNA architecture by inducing bends upon binding.D. Murugesapillai et al, DNA bridging and looping by HMO1 provides a mechanism for stabilizing nucleosome-free chromatin, Nucleic Acids Res (2014) 42 (14): 8996-9004D.
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Rotation of the central stalk against the surrounding alpha3beta3 subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity). The epsilon subunit is located in the stalk region of the F1 complex, and acts as an inhibitor of the ATPase catalytic core. The epsilon subunit can assume two conformations, contracted and extended, where the latter inhibits ATP hydrolysis. The conformation of the epsilon subunit is determined by the direction of rotation of the gamma subunit, and possibly by the presence of ADP.
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This bending in the triple line is unfavorable and is not seen in real-world situations. A theory that preserves the Cassie–Baxter equation while at the same time explaining the presence of the minimized energy state of the triple line hinges on the idea of a precursor film. This film of submicrometer thickness advances ahead of the motion of the droplet and is found around the triple line. Furthermore, this precursor film allows the triple line to bend and take different conformations that were originally considered unfavorable.
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Haemoglobin changes conformation from a high- affinity R state (oxygenated) to a low-affinity T state (deoxygenated) to improve oxygen uptake and delivery.The Bohr effect hinges around allosteric interactions between the hemes of the haemoglobin tetramer, a mechanism first proposed by Max Perutz in 1970. Haemoglobin exists in two conformations: a high-affinity R state and a low-affinity T state. When oxygen concentration levels are high, as in the lungs, the R state is favored, enabling the maximum amount of oxygen to be bound to the hemes.
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Jarrold's research focuses include use of ion-mobility spectrometry to analyze proteins, peptides, clusters, and other biomolecules. Through ion mobility spectrometry, his group was able to see deviations from the native state and different conformations (different protein folding modes). Some of Jarrold's more recent research has investigated the formation of viral capsids by analyzing the intermediates in their formation with charge detection mass spectrometry (CDMS). Jarrold has been involved in the publication of over 250 articles.Jarrold, Martin F. “Publications.” MFJ Research Group, Indiana University Chemistry Department, www.indiana.edu/~nano/publications/.
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The double helix is the dominant tertiary structure for biological DNA, and is also a possible structure for RNA. Three DNA conformations are believed to be found in nature, A-DNA, B-DNA, and Z-DNA. The "B" form described by James D. Watson and Francis Crick is believed to predominate in cells. James D. Watson and Francis Crick described this structure as a double helix with a radius of 10 Å and pitch of 34 Å, making one complete turn about its axis every 10 bp of sequence.
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The chair conformation of six-membered rings have a dihedral angle of 60° between adjacent substituents thus usually making it the most stable conformer. Since there are two possible chair conformation steric and stereoelectronic effects such as the anomeric effect, 1,3-diaxial interactions, dipoles and intramolecular hydrogen bonding must be taken into consideration when looking at relative energies. Conformations with 1,3-diaxial interactions are usually disfavored due to steric congestion and can shift equilibrium to the other chair form (example: 1C4 to 4C1). The size of the substituents greatly affects this equilibrium.
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Proteins that function as morpheeins are illustrated using a dice analogy where one dice can morph into two different shapes, cubic and tetrahedral. The illustrated assemblies apply a rule that the dice face with one spot must contact the dice face with four spots. To satisfy the rule for each dice in an assembly, the cubic dice can only form a tetramer and the tetrahedral dice can only assemble to a pentamer. This is analogous to two different conformations (morpheein forms) of a protein subunit each dictating assembly to a different oligomer.
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The thorax and abdomen are separate and each twin has its own umbilicus and umbilical cord. The union may involve the entire diameter of the head or only a small portion. This suggests that although many different kinds of vulnerabilities are already known in the scientific community, there are an infinite number of variations that can occur. Most of these variations are based on the rotation of one twin's skull to the other and the different phenotype sub-groups of craniopagus twins are based on all these rotational conformations.
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Ancient Greek rhyton in the shape of a mule's head, made by Brygos, early 5th century BC. Jérôme Carcopino Museum, Department of Archaeology, Aleria With its short thick head, long ears, thin limbs, small narrow hooves, and a short mane, the mule shares characteristics of a donkey. In height and body, shape of neck and rump, uniformity of coat, and teeth, it appears horse-like. The mule comes in all sizes, shapes and conformations. There are mules that resemble huge draft horses, sturdy quarter horses, fine-boned racing horses, shaggy ponies and more.
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The sodium glucose cotransporter is original arranged with an outward-facing conformation with open receptors in preparation for 2 sodium ions and glucose to simultaneously bind. Once bound, the protein receptor will change conformation to an occluded conformation, which prevents the dissociation of the sodium ions and glucose. The protein will then change conformations once more to an inward-facing conformation in which allows sodium and glucose will to dissociate. The protein then returns to the outward-facing conformation state, ready to bind more sodium ions and glucose.
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She showed that the peptide hormone glucagon fibrillizes into an antiparallel hydrogen-bonded β-sheet with two coexisting molecular conformations. These studies shed light on the origin of structural polymorphism, water interaction, and metal ion binding. Hong has pioneered the study of plant cell walls using multidimensional ssNMR. These studies revealed the molecular interactions of the polysaccharides in plant cell walls, and helped to revise the conventional model of the primary cell wall structure by proposing a single-network model where cellulose, hemicellulose and pectins all interact with each other.
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The significance of peptide plane flips in the dynamics of the native state has been inferred in some proteins by comparing crystal structures of the same protein in multiple conformations. For example, peptide flips have been described as significant in the catalytic cycle of flavodoxin and in the formation of amyloid structures, where their ability to provide a low-energy pathway between beta sheet and the so-called alpha sheet conformation is suggested to facilitate the early stages of amyloidogenesis. Peptide plane flipping may also be significant in the early stages of protein folding.
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Simplified energy landscape of the world's socioeconomic system and social tipping dynamics at different levels of detail, highlighting factors that influence transitions An energy landscape is a mapping of possible states of a system. The concept is frequently used in physics, chemistry, and biochemistry, e.g. to describe all possible conformations of a molecular entity, or the spatial positions of interacting molecules in a system, or parameters and their corresponding energy levels, typically Gibbs free energy. Geometrically, the energy landscape is the graph of the energy function across the configuration space of the system.
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On May 9, 2008, after Rosetta@home users suggested an interactive version of the distributed computing program, the Baker lab publicly released Foldit, an online protein structure prediction game based on the Rosetta platform. , Foldit had over 59,000 registered users. The game gives users a set of controls (for example, shake, wiggle, rebuild) to manipulate the backbone and amino acid side chains of the target protein into more energetically favorable conformations. Users can work on solutions individually as soloists or collectively as evolvers, accruing points under either category as they improve their structure predictions.
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But segments of proteins, and polypeptides that lack secondary structure, are often assumed to exhibit a random-coil conformation in which the only fixed relationship is the joining of adjacent amino acid residues by a peptide bond. This is not actually the case, since the ensemble will be energy weighted due to interactions between amino acid side-chains, with lower-energy conformations being present more frequently. In addition, even arbitrary sequences of amino acids tend to exhibit some hydrogen bonding and secondary structure. For this reason, the term "statistical coil" is occasionally preferred.
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If most of the protein contains intermolecular hydrogen bonds it is said to be fibrillar, and the majority of its secondary structure will be beta sheets. However, if the majority of the orientation contains intramolecular hydrogen bonds, then the protein is referred to as globular and mostly consists of alpha helices. There are also conformations that consist of a mix of alpha helices and beta sheets as well as a beta helixes with an alpha sheets. The tertiary structure of proteins deal with their folding process and how the overall molecule is arranged.
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The halides arise by direct reaction of the ligand and a nickel halide and offer a relatively cheap, nontoxic and readily available option of the ligand for various applications. There can also be variable conformations of POCOP pertaining to the various R groups branching off of the donor atoms. Thermal ellipsoid plot of Ni(POCOP)Cl compound In most cases the MPOCOP center features a planar MC3O2P2 core. The rigid conformation and square planar geometry of the POCOP ligand allow for systematic changes over the steric and electronic environment at the metal center.
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400px There are situations where seemingly identical conformations are not equal in strain energy. Syn-pentane strain is an example of this situation. There are two different ways to put both of the bonds the central in n-pentane into a gauche conformation, one of which is 3 kcal mol−1 higher in energy than the other. When the two methyl-substituted bonds are rotated from anti to gauche in opposite directions, the molecule assumes a cyclopentane-like conformation where the two terminal methyl groups are brought into proximity.
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Levinthal's paradox is a thought experiment, also constituting a self- reference in the theory of protein folding. In 1969, Cyrus Levinthal noted that, because of the very large number of degrees of freedom in an unfolded polypeptide chain, the molecule has an astronomical number of possible conformations. An estimate of 3300 or 10143 was made in one of his papers (often incorrectly cited as the 1968 paper). For example, a polypeptide of 100 residues will have 99 peptide bonds, and therefore 198 different phi and psi bond angles.
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Lattice models in biophysics represent a class of statistical-mechanical models which consider a biological macromacromolecule (such as DNA, protein, actin, etc.) as a lattice of units, each unit being in different states or conformations. For example, DNA in chromatin can be represented as a one- dimensional lattice, whose elementary units are the nucleotide, base pair or nucleosome. Different states of the unit can be realized either by chemical modifications (e.g. DNA methylation or modifications of DNA-bound histones), or due to quantized internal degrees of freedom (e.g.
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Crete Senesi are literally the "clays of Siena": the distinctive grey colouration of the soil gives the landscape an appearance often described as lunar. This characteristic clay, known as mattaione, represents the sediments of the Pliocene sea which covered the area between 2.5 and 4.5 million years ago. The landscape is characterized by barren and gently undulating hills, solitary oaks and cypresses, isolated farms at the top of the heights, stretches of wood and ponds of rainwater (commonly referred as fontoni, literally "big springs") in the valleys. Badlands and are typical conformations of the land.
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A network of alternative conformations in catalase (Protein Data Bank code: 1gwe) with diverse properties. Multiple phenomena define the network: van der Waals interactions (blue dots and line segments) between sidechains, a hydrogen bond (dotted green line) through a partial-occupancy water (brown), coupling through the locally mobile backbone (black), and perhaps electrostatic forces between the Lys (green) and nearby polar residues (blue: Glu, yellow: Asp, purple: Ser). This particular network is distal from the active site and is therefore putatively not critical for function. Many residues are in close spatial proximity in protein structures.
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This is true for most residues that are contiguous in the primary sequence, but also for many that are distal in sequence yet are brought into contact in the final folded structure. Because of this proximity, these residue's energy landscapes become coupled based on various biophysical phenomena such as hydrogen bonds, ionic bonds, and van der Waals interactions (see figure). Transitions between states for such sets of residues therefore become correlated. This is perhaps most obvious for surface-exposed loops, which often shift collectively to adopt different conformations in different crystal structures (see figure).
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This sequence feature appeared between microsatellite repeats and C:G mononucleotides in all strand-biased domains sequenced. These interruptions in compositional bias adopted highly distorted conformations as shown by their response to nuclease enzymes, presumably due to steric effects of the larger (bicyclic) purines protruding into the complementary strand of smaller (monocyclic) pyridine rings. The sequence TTAA:TTAA was found in the longest such domain of RU, which produced the strongest of all responses to nucleases. That particular strand-biased divergent domain was subcloned and its altered helical structure was studied in greater detail.
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Branch point in a polymer Glycogen, a branched polysaccharideIn polymer chemistry, branching occurs by the replacement of a substituent, e.g., a hydrogen atom, on a monomer subunit, by another covalently bonded chain of that polymer; or, in the case of a graft copolymer, by a chain of another type. Branched polymers have more compact and symmetrical molecular conformations, and exhibit intra-heterogeneous dynamical behavior with respect to the unbranched polymers. In crosslinking rubber by vulcanization, short sulfur branches link polyisoprene chains (or a synthetic variant) into a multiply branched thermosetting elastomer.
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While performing molecular assays involving use of antibodies such as in the Western blot, immunohistochemistry, and ELISA, one should carefully choose antibodies that recognize linear or conformational epitopes. For instance, if a protein sample is boiled, treated with beta- mercaptoethanol, and run in SDS-PAGE for the Western blot, the proteins are essentially denatured and therefore cannot assume their natural three- dimensional conformations. Therefore, antibodies that recognize linear epitopes instead of conformational epitopes are chosen for immunodetection. In contrast, in immunohistochemistry where protein structure is preserved, antibodies that recognize conformational epitopes are preferred.
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Sodium lauryl sulfate, in science referred to as sodium dodecyl sulfate (SDS), is used in cleaning procedures, and is commonly used as a component for lysing cells during RNA extraction and/or DNA extraction, and for denaturing proteins in preparation for electrophoresis in the SDS-PAGE technique.The acronym expands to "sodium dodecyl sulfate-polyacrylamide gel electrophoresis." Denaturation of a protein using SDS In the case of SDS-PAGE, the compound works by disrupting non-covalent bonds in the proteins, and so denaturing them, i.e. causing the protein molecules to lose their native conformations and shapes.
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Nucleic acid helices are recognized in several biological processes like during nucleic acid replication or ribosomal translational decoding. In polymerases and the ribosomal decoding site, the recognition occurs on the minor groove sides of the helical fragments. With or without the use of alternative conformations, protonated or tautomeric forms of the bases, some base pairs with Watson-Crick-like geometries can form and be stabilized. Several of these pairs with Watson-Crick-like geometries extend the concept of isostericity beyond the number of isosteric pairs formed between complementary bases.
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Careful consideration of the BPPS structure shows that the active site, discussed in further detail below, guides the positions and conformations of the isoprenoid functionality of the substrate, while the diphosphate position remains essentially anchored in a single location and conformation. Overall, the pyrophosphate plays an important role in stabilizing the carbocations formed throughout the cyclization in the active site of the enzyme. These interactions and the strategic positioning of pyrophosphate is what is believed to lead to its endo-specific recapture in the final step by the bornyl cation.
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An early model for the role of substituents in pi stacking interactions was proposed by Hunter and Sanders. They used a simple mathematical model based on sigma and pi atomic charges, relative orientations, and van der Waals interactions to qualitatively determine that electrostatics are dominant in substituent effects. According to their model, electron-withdrawing groups reduce the negative quadrupole of the aromatic ring and thereby favor parallel displaced and sandwich conformations. Contrastingly, electron donating groups increase the negative quadrupole, which may increase the interaction strength in a T-shaped configuration with the proper geometry.
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The authors also considered a homodesmotic dissection of benzene into ethylene and 1,3-butadiene and compared these interactions in a sandwich with benzene. Their calculation indicates that the interaction energy between benzene and homodesmotic benzene is higher than that of a benzene dimer in both sandwich and parallel displaced conformations, again highlighting the favorability of localized pi-bond interactions. These results strongly suggest that aromaticity is not required for pi stacking interactions in this model. Even in light of this evidence, Grimme concludes that pi stacking does indeed exist.
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Characteristics indicative of the 3-dimensional structure of proteins can be probed with mass spectrometry in various ways. By using chemical crosslinking to couple parts of the protein that are close in space, but far apart in sequence, information about the overall structure can be inferred. By following the exchange of amide protons with deuterium from the solvent, it is possible to probe the solvent accessibility of various parts of the protein. Hydrogen-deuterium exchange mass spectrometry has been used to study proteins and their conformations for over 20 years.
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It is thought that they may be involved in the process that confers specific chromatin conformations to transcribable regions in the genome. The SMART signature describes a nucleosomal binding domain, which facilitates binding of proteins to nucleosomes in chromatin. The domain is most commonly found in the high mobility group (HMG) proteins, HMG14 and HMG17, however, it is also found in other proteins which bind to nucleosomes, e.g. NBP-45. NBP-45 is a nucleosomal binding protein, first identified in mice, which is related to HMG14 and HMG17.
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This method is an example of using cis-acting elements where the two genes are under the same promoter elements and are transcribed into a single messenger RNA molecule. The mRNA is then translated into protein. It is important that both proteins be able to properly fold into their active conformations and interact with their substrates despite being fused. In building the DNA construct, a segment of DNA coding for a flexible polypeptide linker region is usually included so that the reporter and the gene product will only minimally interfere with one another.
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Heterocycles (dihydrofuran, dihydrothiophene, dihydropyrrole, tetrahydropyran) give the alcohols in ≥99% ee; the high ee's reflect their constrained conformations. It adds to alkynes to form the corresponding vinyldiisopinocampheylboranes :600px In a highly stereoselective reaction, allyldiisopinocampheylboranes converts aldehydes to the homologated alcohols, rapidly even at -100 °C.Raj K. Dhar, Kanth V. B. Josyula, Robert Todd “Diisopinocampheylborane” in Encyclopedia of Reagents for Organic Synthesis, 2006, John Wiley & Sons, New York. . Article Online Posting Date: September 15, 2006 The alkyldiisopinocampheylboranes, which result from the addition to alkenes, usefully react with a range of different reagents.
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In addition to this, the evolutionary relationships between ligand-dependent receptors did not make much sense as closely related receptors of subfamilies bound ligands originating from entirely different biosynthetic pathways (e.g. TRs and RARs). On the other hand, subfamilies that are not evolutionarily related bind similar ligands (RAR and RXR both bind all-trans and 9-cis retinoic acid respectively). # In 1997, it was discovered that nuclear receptors did not exist in static off and on conformations, but that a ligand could alter the equilibrium between the two states.
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The preference for one conformation over another can be characterized by ΔG0, the free energy difference, which can, at some level, be estimated from conformational analysis. The free energy difference between the two transition states of each conformation on its path to product formation is given by ΔΔG‡. The value of ΔG0 between not just one, but many accessible conformations is the underlying energetic impetus for reactions occurring from the most stable ground state conformation and is the crux of the peripheral attack model outlined below.Seeman, J. I. Chem. Rev.
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He attended King's College London, graduating with a first-class honours degree in Physics in 1967. In 1967, he visited Israel for the first time. Together with his Israeli wife, Rina, a multimedia artist, he left to study at Cambridge, where their three children were born. Levitt was a PhD student in Computational biology at Peterhouse, Cambridge, and was based at the Laboratory of Molecular Biology from 1968 to 1972, where he developed a computer program for studying the conformations of molecules that underpinned much of his later work.
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ArsA homologues are found in bacteria, archaea and eukarya (both animals and plants), but there are far fewer of them in the databases than ArsB proteins, suggesting that many ArsB homologues function by a pmf-dependent mechanism, probably an arsenite:H+ antiport mechanism. In the E. coli ArsAB transporter, both ArsA and ArsB recognize and bind their anionic substrates. A model has been proposed in which ArsA alternates between two virtually exclusive conformations. In one, (ArsA1) the A1 site is closed but the A2 site is open, but in the other (ArsA2) the opposite is true.
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Antimonite [Sb(III)] sequesters ArsA in the ArsA1 conformation which catalyzes ATP hydrolysis at A2 to drive ArsA between conformations that have high (nucleotide-bound ArsA) and low (nucleotide-free ArsA) affinity for antimonite. It is proposed that ArsA uses this process to sequester Sb(III) and eject it into the ArsB channel. In the case of ArsAB, at the interface of these two halves are two nucleotide-binding domains and a metalloid-binding domain. Cys-113 and Cys-422 have been shown to form a high- affinity metalloid binding site.
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Stirling Hoard, Scotland. There are several types of rigid gold and sometimes bronze necklaces and collars of the later European Bronze Age, from around 1200 BC, many of which are classed as "torcs". They are mostly twisted in various conformations, including the "twisted ribbon" type, where a thin strip of gold is twisted into a spiral. Other examples twist a bar with a square or X section, or just use round wire, with both types in the three 12th– or 11th-century BC specimens found at Tiers Cross, Pembrokeshire, Wales.
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Drosophila Orb2 binds to genes implicated in long-term memory. An isoform of CPEB found in the neurons of the sea slug Aplysia californica, as well as in Drosophila, mice, and humans, contains an N-terminal domain not found in other isoforms that shows high sequence similarity to prion proteins. Experiments with the Aplysia isoform expressed in yeast reveal that CPEB has a key property associated with prions: it can cause other proteins to assume alternate protein conformations that are heritable in successive generations of yeast cells. Furthermore, the functional RNA-binding form of the CPEB protein may be the prion-like state.
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Dasatinib binds to Abl with less stringent conformational requirements than imatinib so it exhibits increased potency but reduced selectivity compared to imatinib. Dasatinib binds both the active and inactive conformation of Abl kinase, contrary to the binding of most other TKIs to the active form only. Compounds that target the active conformation have been identified but the binding site in all the hundreds of human protein kinases is very similar. Therefore, there is a considerably greater scope for dissimilarities between the inactive conformations so the efforts to discover highly selective kinase inhibitors are being directed towards molecules that bind to the inactive conformation.
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Free mercury ions can bind to metalloproteins, particularly those with cysteine residues, and can cause incorrect conformations resulting in function loss. This can cause death in many bacteria, as can many other heavy metals, and thus, needs to be removed from the cell or transformed into a chemically inert form. Mercury(II) reductase takes Hg2+ and catalyzes its reduction into Hg0 which is then released from the cell as a vapour. Mercury in its elemental form does not have the ability to form stable complexes with amino acid residues in proteins so is less dangerous than its ionic form.
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While there is no small-angle strain present in medium-sized rings, there does exist something called large-angle strain. Some angle and torsional strain is used by rings with more than nine members to relieve some of the distress caused by transannular strain. As the plot to the left indicates, the relative energies of cycloalkanes increases as the size of the ring increases, with a peak at cyclononane (with nine members in its ring.) At this point, the flexibility of the rings increases with increasing size; this allows for conformations that can significantly mitigate transannular interactions.
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This movie depicts the 3-D structures of each of the representative conformations of the Markov State Model of Pin1 WW domain. Conformational ensembles, also known as structural ensembles are experimentally constrained computational models describing the structure of intrinsically unstructured proteins. Such proteins are flexible in nature, lacking a stable tertiary structure, and therefore cannot be described with a single structural representation. The techniques of ensemble calculation are relatively new on the field of structural biology, and are still facing certain limitations that need to be addressed before it will become comparable to classical structural description methods such as biological macromolecular crystallography.
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G protein classes are defined based on the sequence and function of their alpha subunits, which in mammals fall into several sub-types: G(S)alpha, G(Q)alpha, G(I)alpha, transducin and G(12)alpha; there are also fungal and plant classes of alpha subunits. The alpha subunit consists of two domains: a GTP-binding domain and a helical insertion domain (). The GTP-binding domain is homologous to Ras-like small GTPases, and includes switch regions I and II, which change conformation during activation. The switch regions are loops of alpha-helices with conformations sensitive to guanine nucleotides.
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Since this is a tertiary amide, it exists in a cis/trans mixture, which underlies the two conformations of kalkitoxin. Structure (c) is a string of two methylene groups, then a methine group bearing a high-field methyl group. The next two groups identified (d,e) are identical and opposing strings of CH2-CH-CH3, however the left grouping's methylene protons experience greater deshielding, due to their proximity to the adjacent imine. Deshielding is an effect of a nearby electronegative atom withdrawing electron density from a given atom nucleus, eliciting an increased chemical shift as measured by NMR.
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That is, there is no directional correlation along the chain for distances greater than this distance, referred to as a Kuhn length. These non-straight regions evoke the concept of ‘kinks’ and are in fact a manifestation of the random-walk nature of the chain. Since a kink is composed of several isoprene units, each having three carbon-carbon single bonds, there are many possible conformations available to a kink, each with a distinct energy and end-to-end distance. Over time scales of seconds to minutes, only these relatively short sections of the chain, i.e.
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Interactions between VP1 molecules within a pentamer involve extensive binding surfaces, mediated in part by interactions between edge beta-strands. The VP1 C-terminus is disordered and forms interactions between neighboring pentamers in the assembled capsid. The flexibility of the C-terminal arm will enable it to adopt different conformations in the six distinct interaction environments imposed by the symmetry of the icosahedral assembly. The C-terminus also contains a basic nuclear localization sequence, while the N-terminus - which is oriented toward the center of the assembled capsid - contains basic residues that facilitate non-sequence-specific interactions with DNA.
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This allows chains to assume other possibly, energetically equivalent conformations with a small amount of disentangling. As a result, the majority of SMPs will form compact, random coils because this conformation is entropically favored over a stretched conformation. Polymers in this elastic state with number average molecular weight greater than 20,000 stretch in the direction of an applied external force. If the force is applied for a short time, the entanglement of polymer chains with their neighbors will prevent large movement of the chain and the sample recovers its original conformation upon removal of the force.
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The hemolysin portion of the protein then binds to the target membrane and inserts itself into the bilayer. The adenylate cyclase (AC) domain is then translocated across the cytoplasmic membrane into the cytoplasm. Translocation of the AC domain is independent of cytotoxic pore- forming activity, as these two activities require to toxin to adopt different conformations. The transiently opened pores do, however, contribute to AC domain function by potassium leakage and calcium influx into the target cell, which slows endocytosis of CR3/adenylate cyclase toxin clusters, also, the CR3/toxin complex is mobilized by detachment from the cytoskeleton.
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Utilizing different amounts of ancillary ligand, the researcher can toggle between a number of complex conformations. In the closed state, the metal center is fully chelated to both ligands. With the addition of one equivalent of the selected ancillary ligand, a semi-open complex is formed which involves one ligand fully chelated and the other bound to the metal only through the phosphorus moiety. In mixed ligand systems, the ancillary ligand will selectively displace the weakest Y–M bond - an important feature for the more sophisticated catalytic structures (based on the halide- induced ligand rearrangement (HILR) reaction and triple-layer geometries).
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The invariance properties of molecular descriptors can be defined as the ability of the algorithm for their calculation to give a descriptor value that is independent of the particular characteristics of the molecular representation, such as atom numbering or labeling, spatial reference frame, molecular conformations, etc. Invariance to molecular numbering or labeling is assumed as a minimal basic requirement for any descriptor. Two other important invariance properties, translational invariance and rotational invariance, are the invariance of a descriptor value to any translation or rotation of the molecules in the chosen reference frame. These last invariance properties are required for the 3D-descriptors.
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To a large extent, portions of nucleotide repeats are quite often observed as part of rare DNA combinations. The three main repeats which are largely found in particular DNA constructs include the closely precise homopurine-homopyrimidine inverted repeats, which is otherwise referred to as H palindromes, a common occurrence in triple helical H conformations that may comprise either the TAT or CGC nucleotide triads. The others could be described as long inverted repeats having the tendency to produce hairpins and cruciform, and finally direct tandem repeats, which commonly exist in structures described as slipped-loop, cruciform and left-handed Z-DNA.
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A – Active site B – Allosteric site C – Substrate D – Inhibitor E – Enzyme This is a diagram of allosteric regulation of an enzyme. Many allosteric effects can be explained by the concerted MWC model put forth by Monod, Wyman, and Changeux, or by the sequential model described by Koshland, Nemethy, and Filmer. Both postulate that protein subunits exist in one of two conformations, tensed (T) or relaxed (R), and that relaxed subunits bind substrate more readily than those in the tense state. The two models differ most in their assumptions about subunit interaction and the preexistence of both states.
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The energy barrier for the exchange is quite low and occurs even at very low temperatures. Infrared spectroscopy has been used to obtain information about the different conformations of the methanium ion. The IR spectrum of plain methane has two C-H bands from symmetric and asymmetric stretching at around 3000 cm−1 and two bands around 1400 cm−1 from symmetrical and asymmetric bending vibrations. In the spectrum of three asymmetric stretching vibrations are present around 2800–3000 cm−1, a rocking vibration at 1300 cm−1, and a bending vibration at 1100 1300 cm−1.
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ICM stands for Internal Coordinate Mechanics and was first designed and built to predict low-energy conformations of molecules by sampling the space of internal coordinates (bond lengths, bond angles and dihedral angles) defining molecular geometry. In ICM each molecule is constructed as a tree from an entry atom where each next atom is built iteratively from the preceding three atoms via three internal variables. The rings kept rigid or imposed via additional restraints. ICM also is a programming environment for various tasks in computational chemistry and computational structural biology, sequence analysis and rational drug design.
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The structure of the PDK3/L2 complex has been elucidated, and there are several key features. When the L2 domain binds to PDK3, it induces a “cross-tail” conformation in PDK3, thereby stimulating activity. There are three crucial residues, Leu-140, Glu-170, and Glu-179, in the C-terminal domain that are crucial for this interaction. Structural studies have indicated that L2 binding stimulates activity by disrupting the closed conformation, or ATP lid, to remove product inhibition. The PDK3 subunits are in one of two conformations; one subunit exists as an “open” subunit, while the other subunit is “closed”.
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Figure showing the various conformational changes which are observed in circular DNA at different pH. At a pH of about 12 (alkaline), there is a dip in the sedimentation coefficient, followed by a relentless increase up to a pH of about 13, at which pH the structure converts into the mysterious "Form IV". The topological properties of circular DNA are complex. In standard texts, these properties are invariably explained in terms of a helical model for DNA, but in 2008 it was noted that each topoisomer, negative or positive, adopts a unique and surprisingly wide distribution of three-dimensional conformations.
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It has been shown that for most proteins the coordination number of the lattice used should fall between 3 and 20, although most commonly used lattices have coordination numbers at the lower end of this range. Lattice shape is an important factor in the accuracy of lattice protein models. Changing lattice shape can dramatically alter the shape of the energetically favorable conformations. It can also add unrealistic constraints to the protein structure such as in the case of the parity problem where in square and cubic lattices residues of the same parity (odd or even numbered) cannot make hydrophobic contact.
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Rowena Ball and John Brindley (2016): "The life story of hydrogen peroxide III: Chirality and physical effects at the dawn of life". Origins of Life and Evolution of Biospheres, volume 46, pages 81–93 Conversely, the energy barrier may be so high that the easiest way to overcome it would require temporarily breaking and then reforming or more bonds of the molecule. In that case, the two isomers usually are stable enough to be isolated and treated as distinct substances. These isomers are then said to be different configurational isomers or "configurations" of the molecule, not just two different conformations.
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Two parts of a molecule that are connected by just one single bond can rotate about that bond. While the bond itself is indifferent to that rotation, attractions and repulsions between the atoms in the two parts normally cause the energy of the whole molecule to vary (and possibly also the two parts to deform) depending on the relative angle of rotation φ between the two parts. Then there will be one or more special values of φ for which the energy is at a local minimum. The corresponding conformations of the molecule are called rotational isomers or rotamers.
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Thus, for example, in an ethane molecule –, all the bond angles and length are narrowly constrained, except that the two methyl groups can independently rotate about the C–C axis. Thus, even if those angles and distances are assumed fixed, there are infinitely many conformations for the ethane molecule, that differ by the relative angle φ of rotation between the two groups. The feeble repulsion between the hydrogen atoms in the two methyl groups causes the energy to minimized for three specific values of φ, 120° apart. In those configurations, the six planes H–C–C or C–C–H are 60° apart.
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At first, he analyzed the sequences of proteins and then uncovered details of the modified genetic code in mitochondria. In 1978, he decided to apply protein chemical methods to membrane proteins. In this way, Walker characterized the subunit composition of proteins in the mitochondrial membrane and the DNA sequence of the mitochondrial genome. His landmark crystallographic studies of the F1-ATPase, the catalytic region of the ATP synthase (done in collaboration with crystallographer Andrew Leslie), from bovine heart mitochondria revealed the three catalytic sites in three different conformations imposed by the position of the asymmetric central stalk.
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During substrate binding, the NAD-BD moves significantly. This movement has two components, rotating along the long axis of a helix at the back of the NAD-BD, called "the pivot helix", and twisting about the antenna in a clockwise fashion. A comparison of the open and closed conformations of GLUD1 reveals changes in the small helix of the descending strand of the antenna, which seems to recoil as the catalytic cleft opens. Closure of one subunit is associated with distortion of the small helix of the descending strand that is pushed into the antenna of the adjacent subunit.
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Forisomes function as valves in sieve tubes of the phloem system, by reversibly changing shape between low-volume ordered crystalloid spindles and high-volume disordered spherical conformations. The change from ordered to disordered conformation involves tripling of the protein's volume, loss of birefringence present in the crystalline phase, 120% radial expansion and 30% longitudinal shrinkage. In Vicia it was shown that forisomes are associated to the endoplasmic reticulum at sieve plates. There are evidences that the forisomes's behavior could depend on Ca2+ changes provoked by Ca2+-permeable ion channels, located on the endoplasmic reticulum and plasma membrane of sieve elements.
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Structure of molecular beacons in their native conformations (top) or hybridized with a DNA strand (bottom) Molecular beacons, or molecular beacon probes, are oligonucleotide hybridization probes that can report the presence of specific nucleic acids in homogenous solutions. Molecular beacons are hairpin-shaped molecules with an internally quenched fluorophore whose fluorescence is restored when they bind to a target nucleic acid sequence. This is a novel non-radioactive method for detecting specific sequences of nucleic acids. They are useful in situations where it is either not possible or desirable to isolate the probe-target hybrids from an excess of the hybridization probes.
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However, NMR experiments are able to provide information from which a subset of distances between pairs of atoms can be estimated, and the final possible conformations for a protein are determined by solving a distance geometry problem. Dual polarisation interferometry is a quantitative analytical method for measuring the overall protein conformation and conformational changes due to interactions or other stimulus. Circular dichroism is another laboratory technique for determining internal β-sheet / α-helical composition of proteins. Cryoelectron microscopy is used to produce lower-resolution structural information about very large protein complexes, including assembled viruses;Branden and Tooze, pp. 340–41.
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One of the original experiments performed by Winston and Holness was measuring the rate of oxidation in trans and cis substituted rings using a chromium catalyst. The large tert-butyl group used locks the conformation of each molecule, placing it equatorial (cis compound shown). Possible chair conformations of cis-4-tert-butyl-1-cyclohexanol It was observed that the cis compound underwent oxidation at a much faster rate than the trans compound. The proposition was that the large hydroxyl group in the axial position was disfavored and formed the carbonyl more readily to relieve this strain.
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Metal ions promote this reaction by first coordinating the phosphate oxygen and later stabling the oxyanion. The second mechanism also follows a SN2 displacement, but the nucleophile comes from water or exogenous hydroxyl groups rather than RNA itself. The smallest ribozyme is UUU, which can promote the cleavage between G and A of the GAAA tetranucleotide via the first mechanism in the presence of Mn2+. The reason why this trinucleotide rather than the complementary tetramer catalyze this reaction may be because the UUU-AAA pairing is the weakest and most flexible trinucleotides among the 64 conformations, which provides the binding site for Mn2+.
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Proteins are generally thought to adopt unique structures determined by their amino acid sequences, as outlined by Anfinsen's dogma. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these states occur on a variety of length scales (tenths of Å to nm) and time scales (ns to s), and have been linked to functionally relevant phenomena such as allosteric signaling and enzyme catalysis. The study of protein dynamics is most directly concerned with the transitions between these states, but can also involve the nature and equilibrium populations of the states themselves.
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However, coupled conformational heterogeneity is also sometimes evident in secondary structure. For example, consecutive residues and residues offset by 4 in the primary sequence often interact in α helices. Also, residues offset by 2 in the primary sequence point their sidechains toward the same face of β sheets and are close enough to interact sterically, as are residues on adjacent strands of the same β sheet. An "ensemble" of 44 crystal structures of hen egg white lysozyme from the Protein Data Bank, showing that different crystallization conditions lead to different conformations for various surface-exposed loops and termini (red arrows).
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Thus, a PES can be drawn mapping the potential energy E of a water molecule as a function of two geometric parameters, q1= O-H bond length and q2=H-O-H bond angle. The lowest point on such a PES will define the equilibrium structure of a water molecule. Figure 3: PES for water molecule: Shows the energy minimum corresponding to optimized molecular structure for water- O-H bond length of 0.0958nm and H-O-H bond angle of 104.5° The same concept is applied to organic compounds like ethane, butane etc. to define their lowest energy and most stable conformations.
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It has little secondary structure in solution but assumes distinct conformations when bound to substrates such as DNA or other proteins. HMGA1 proteins have high amounts of diverse posttranslational modifications and are located mainly in the nucleus, especially in heterochromatin, but also in mitochondria and the cytoplasm. Recently it has been shown that HMGA1 proteins, HMGA1a and HMGA1b, can cross-link DNA fibers in vitro and can induce chromatin clustering in vivo suggesting a structural role of HMGA1 proteins in heterochromatin organization. At least seven transcript variants encoding two different isoforms (HMGA1a, HMGA1b) have been found for this gene.
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Another approach is to describe the hydrophobic features of the protein using turns in the main-chain atoms. Yet another approach is to use a Fourier shape descriptor technique. Whereas the shape complementarity based approaches are typically fast and robust, they cannot usually model the movements or dynamic changes in the ligand/ protein conformations accurately, although recent developments allow these methods to investigate ligand flexibility. Shape complementarity methods can quickly scan through several thousand ligands in a matter of seconds and actually figure out whether they can bind at the protein's active site, and are usually scalable to even protein-protein interactions.
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Correct folding requires proteins to assume one particular structure from a constellation of possible but incorrect conformations. The failure of polypeptides to adopt their proper structure is a major threat to cell function and viability. Consequently, elaborate systems have evolved to protect cells from the deleterious effects of misfolded proteins. Cells mainly deploy three mechanisms to counteract misfolded proteins: up-regulating chaperones to assist protein refolding, proteolytic degradation of the misfolded/damaged proteins involving ubiquitin–proteasome and autophagy–lysosome systems, and formation of detergent-insoluble aggresomes by transporting the misfolded proteins along microtubules to a region near the nucleus.
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207:201-10 These protein structures are usually related to one single physiological protein activity. This hypothesis was, however, challenged by observations that proteins could fold in two alternative conformations, such as the prion proteins which exist in a physiologically active cellular form and an insoluble form. Extending the concept of a protein that exists in a soluble and an insoluble form, for the bacterial transcription factor RfaH two entirely different structures were observed to coexist in solution. RfaH is a two-domain protein, the C-terminal domain (CTD) of which can fold into alpha- helical and, alternatively, into beta-barrel form.
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The Barton reaction, also known as the Barton nitrite ester reaction, is a photochemical reaction that involves the photolysis of an alkyl nitrite to form a δ-nitroso alcohol. Discovered in 1960, the reaction is named for its discoverer, Nobel Laureate Sir Derek Barton. Barton's Nobel Prize in Chemistry in 1969 was awarded for his work on understanding conformations of organic molecules, work which was key to realizing the utility of the Barton Reaction. The Barton reaction involves a homolytic RO–NO cleavage, followed by δ-hydrogen abstraction, free radical recombination, and tautomerization to form an oxime.
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The metal also has a flexible coordination geometry, which allows proteins using it to rapidly shift conformations to perform biological reactions. Two examples of zinc-containing enzymes are carbonic anhydrase and carboxypeptidase, which are vital to the processes of carbon dioxide () regulation and digestion of proteins, respectively. In vertebrate blood, carbonic anhydrase converts into bicarbonate and the same enzyme transforms the bicarbonate back into for exhalation through the lungs. Without this enzyme, this conversion would occur about one million times slower at the normal blood pH of 7 or would require a pH of 10 or more.
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He was the first to demonstrate the use of genetic code engineering as a tool for the creation of therapeutic proteins and ribosomally synthetized peptide-drugs. He has succeeded with innovative engineering of biomaterials, in particular photoactivatable mussel-based underwater adhesives. Ned Budisa made seminal contributions to our understanding of the role of methionine oxidation in prion protein aggregation and has discovered the roles of proline side chain conformations (endo-exo isomerism) in translation, folding and stability of proteins. Together with his co-worker Vladimir Kubyshkin, the new-to-nature hydrophobic polyproline-II helix foldamer was designed.
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KRP is also an important structural regulator of myosin filaments. Smooth muscle myosin, under physiological conditions in vitro, can adapt two relatively and different stable conformations. When the myosin is in the extended conformation, it is active and able to combine with other myosin molecules to form thick filaments which are fundamental for effective contraction. Upon ATP binding, the rod part of unphosphorylated myosin molecule folds into thirds, so that the head –rod junction is brought close to the middle of the rod and stabilized there, presumable by interacting with both the 20 KDa light chains and the neck region.
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492 This last achievement demonstrates for the first time, without any ambiguity, the molecular basis of such an activity, commonly used in hospital medicine. This breakthrough in glyco-chemistry has led to the concept of conformational flexibility,B. Casu, J. Choay, D.R. Ferro, G. Gatti, J.-C. Jacquinet, M. Petitou, A. Provasoli, M. Ragazzi, P. Sinaÿ, G. Torri, « Controversial glycosaminoglycan conformations », Nature, 1986, 322, p. 215-16B. Casu, M. Petitou, M. Provasoli, P. Sinaÿ, « Conformational flexibility : a new concept for explaining binding and biological properties of iduronic acid-containing glycosaminoglycans », Trends in Biochemical Sciences, 1988, 13, p.
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The P-type ATPases, also known as E1-E2 ATPases, are a large group of evolutionarily related ion and lipid pumps that are found in bacteria, archaea, and eukaryotes. P-type ATPases are α-helical bundle primary transporters named based upon their ability to catalyze auto- (or self-) phosphorylation (hence P) of a key conserved aspartate residue within the pump and their energy source, adenosine triphosphate (ATP). In addition, they all appear to interconvert between at least two different conformations, denoted by E1 and E2. P-type ATPases fall under the P-type ATPase (P-ATPase) Superfamily (TC# 3.
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The structure minimizing repulsive steric interactions provides the observed product by having the lowest barrier to a transition state for the reaction. Though no external attack by a reagent occurs, this reaction can be thought of similarly to those modeled with peripheral attack; the lowest energy conformation is the most likely to react for a given reaction. 550px The lowest energy conformations of macrocycles also influence intramolecular reactions involving transannular bond formation. In the intramolecular Michael addition sequence below, the ground state conformation minimizes transannular interactions by placing the sp2 centers at the appropriate vertices, while also minimizing diaxial interactions.
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Both of these switches have characteristic folding, correspond to specific regions on the RhoA coil and are uniformly stabilized via hydrogen bonds. The conformations of the Switch domains are modified depending on the binding of either GDP or GTP to RhoA. The nature of the bound nucleotide and the ensuing conformational modification of the Switch domains dictates the ability of RhoA to bind or not with partner proteins (see below). The primary protein sequences of members of the Rho family are mostly identical, with the N-terminal containing most of the protein coding for GTP binding and hydrolysis.
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This is a distinguishing feature between Thermoplasma volcanium and Thermoplasma acidophilum, which has a GC content about 7% larger than that of Thermoplasma volcanium. No significant correlation has been seen between optimum growth temperature (OGT) and GC content. Genomic sequencing of several archaea has demonstrated a positive correlation between OGT and the presence of specific dinucleotide combinations of purines and pyrimidines. The DNA structure of Thermoplasma volcanium has greater flexibility than other archaeal DNA due to an increased presence of purine/pyrimidine conformations, as compared to hyperthermophilic archaea that contain a majority of purine/purine or pyrimidine/pyrimidine pairings.
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The Aβ monomer generally assumes an α-helical formation in aqueous solution, but can reversibly transition between α-helix and β-sheet structures at varying polarities. Atomic force microscopy captured images of Aβ channel structures that facilitated calcium uptake and subsequent neuritic degeneration. Molecular dynamics simulations of Aβ in lipid bilayers suggest that Aβ adopts a β-sheet-rich structure within lipid bilayers that gradually evolves to result in a wide variety of relaxed channel conformations. In particular, data support the organization of Aβ channels in β-barrels, structural formations commonly seen in transmembrane pore-forming toxins including anthrax.
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Nonspecific Aβ channel blockers including tromethamine (Tris) and Zn2+ have successfully inhibited Aβ cytotoxicity. Least-energy molecular models of the Aβ channel have been used to create polypeptide segments to target the mouth of the Aβ pore, and these selective Aβ channel blockers have also been shown to inhibit Aβ cytotoxicity. Structural modeling of Aβ channels, however, suggests that the channels are highly polymorphic, with the ability to move and change size and shape within the lipid membrane. The broad range of conformations adopted by the Aβ channel makes design of a specific, highly effective Aβ channel blocker difficult.
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The model is useful in describing hemoglobin's sigmoidal binding curve. The KNF model (or induced fit model or sequential model) arose to address the possibility of differential binding states. Developed by Koshland, Némethy and Filmer in 1966, the KNF model describes cooperativity as a sequential process, where ligand binding alters the conformation, and thus the affinity, of proximal subunits of the protein, resulting in several different conformations that have varying affinities for a given ligand. This model suggests that the MWC model oversimplifies cooperativity in that it does not account for conformational changes of individual binding sites, opting instead to suggest a single, whole-protein conformational change.
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Staggered conformation image right in Newman projection Eclipsed conformation In organic chemistry, a staggered conformation is a chemical conformation of an ethane-like moiety abcX–Ydef in which the substituents a, b, and c are at the maximum distance from d, e, and f. This requires the torsion angles to be 60°. Such a conformation exists in any open chain single chemical bond connecting two sp3-hybridised atoms, and is normally a conformational energy minimum. For some molecules such as those of n-butane, there can be special versions of staggered conformations called gauche and anti; see first Newman projection diagram in Conformational isomerism.
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In bioinformatics, the root-mean-square deviation of atomic positions (or simply root-mean-square deviation, RMSD) is the measure of the average distance between the atoms (usually the backbone atoms) of superimposed proteins. Note that RMSD calculation can be applied to other, non-protein molecules, such as small organic molecules. In the study of globular protein conformations, one customarily measures the similarity in three-dimensional structure by the RMSD of the Cα atomic coordinates after optimal rigid body superposition. When a dynamical system fluctuates about some well-defined average position, the RMSD from the average over time can be referred to as the RMSF or root mean square fluctuation.
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For RNA, the differences in chemical structure and helix geometry make this assignment more technically difficult, but still possible. The sequential walking methodology is not possible for non-double helical nucleic acid structures, nor for the Z-DNA form, making assignment of resonances more difficult. Parameters taken from the spectrum, mainly NOESY cross-peaks and coupling constants, can be used to determine local structural features such as glycosidic bond angles, dihedral angles (using the Karplus equation), and sugar pucker conformations. The presence or absence of imino proton resonances, or of coupling between 15N atoms across a hydrogen bond, indicates the presence or absence of basepairing.
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NMR is also useful for investigating nonstandard geometries such as bent helices, non- Watson–Crick basepairing, and coaxial stacking. It has been especially useful in probing the structure of natural RNA oligonucleotides, which tend to adopt complex conformations such as stem-loops and pseudoknots. Interactions between RNA and metal ions can be probed by a number of methods, including observing changes in chemical shift upon ion binding, observing line broadening for paramagnetic ion species, and observing intermolecular NOE contacts for organometallic mimics of the metal ions. NMR is also useful for probing the binding of nucleic acid molecules to other molecules, such as proteins or drugs.
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Z-RNA to resemble, but not be identical, to that of Z-DNA.Popenda, M., J. Milecki, and R.W. Adamiak, High salt solution structure of a left-handed RNA double p. 4044-54. The structure of the complex of a Zalpha domain with Z-RNA under close to physiological salt concentrations however suggests a structure much closer to the Z-DNA conformation and points to two forms of Z-RNA (low and high salt conformations) Placido, D., B.A. Brown, 2nd, K. Lowenhaupt, A. Rich, and A. Athanasiadis, A left-handed RNA double helix bound by the Z alpha domain of the RNA-editing enzyme ADAR1. Structure, 2007.
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Exciplexes provide one of the three dynamic mechanisms by which fluorescence is quenched. A regular exciplex has some charge-transfer (CT) character, and in the extreme case there are distinct radical ions with unpaired electrons. If the unpaired electrons can spin-pair to form a covalent bond, then the covalent bonding interaction can lower the energy of the charge transfer state. Strong CT stabilisation has been shown to lead to a conical intersection of this exciplex state with the ground state in a balance of steric effects, electrostatic interactions, stacking interactions, and relative conformations that can determine the formation and accessibility of bonded exciplexes.
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It is just a small part of the secretions made by SCO and remains a matter of speculation, probably involved in many physiological functions as clearance of monoamines, detoxification of the CSF, neuronal surviving or the control of water balance. The glycoproteins forming RF can be found in three conformations, the first on is when the material aggregates over the SCO cilia, the so-called pre-RF, the second and most studied form known as the proper RF which is a cylindrical regular structure, and finally a third and final form, massa caudalis, known as the final distribution and the final assembly of the proteins.
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Formation of PSI+ prion causes S. cerevisiae cells with nonsense-mutation in ade1 gene to convert red pigment (colony below) into a colourless compound, causing colonies to become white (above) A fungal prion is a prion that infects fungal hosts. Fungal prions are naturally occurring proteins that can switch between multiple, structurally distinct conformations, at least one of which is self-propagating and transmissible to other prions. This transmission of protein state represents an epigenetic phenomenon where information is encoded in the protein structure itself, instead of in nucleic acids. Several prion-forming proteins have been identified in fungi, primarily in the yeast Saccharomyces cerevisiae.
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Depending on ring size, the three- dimensional shapes of particular cyclic structures—typically rings of 5-atoms and larger—can vary and interconvert such that conformational isomerism is displayed. Indeed, the development of this important chemical concept arose, historically, in reference to cyclic compounds. For instance, cyclohexanes—six membered carbocycles with no double bonds, to which various substituents might be attached, see image—display an equilibrium between two conformations, the chair and the boat, as shown in the image. The chair conformation is the favored configuration, because in this conformation, the steric strain, eclipsing strain, and angle strain that are otherwise possible are minimized.
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Richardson and coworkers designed a 79-residue protein with no sequence homology to a known protein. In the 1990s, the advent of powerful computers, libraries of amino acid conformations, and force fields developed mainly for molecular dynamics simulations enabled the development of structure-based computational protein design tools. Following the development of these computational tools, great success has been achieved over the last 30 years in protein design. The first protein successfully designed completely de novo was done by Stephen Mayo and coworkers in 1997, and, shortly after, in 1999 Peter S. Kim and coworkers designed dimers, trimers, and tetramers of unnatural right-handed coiled coils.
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The structure shown is that of myoglobin, PDB id: 1mbn. The goal of protein design is to find a protein sequence that will fold to a target structure. A protein design algorithm must, thus, search all the conformations of each sequence, with respect to the target fold, and rank sequences according to the lowest- energy conformation of each one, as determined by the protein design energy function. Thus, a typical input to the protein design algorithm is the target fold, the sequence space, the structural flexibility, and the energy function, while the output is one or more sequences that are predicted to fold stably to the target structure.
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R262 also plays a role in substrate binding by stabilizing the partly unwound TM1' helix. Modeling CaiT from P. mirabilis in the outward-open and closed states on the corresponding structures of the related symporter BetP revealed alternating orientations of the buried R262 side chain, which mimic sodium binding and unbinding in the Na+-coupled substrate symporters. A similar mechanism may be operative in other Na+/H+-independent transporters, in which a positively charged amino acid replaces the cotransported cation. The oscillation of the R262 side chain in CaiT indicates how a positive charge triggers the change between outward-open and inward-open conformations.
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It breaks the protein folding problem into three separate problems: modeling the protein conformation, defining the energetic properties of the amino acids as they interact with one another to find said conformation, and developing an efficient algorithm for the prediction of these conformations. It is done by classifying amino acids in the protein as either hydrophobic or polar and assuming that the protein is being folded in an aqueous environment. The lattice statistical model seeks to recreate protein folding by minimizing the free energy of the contacts between hydrophobic amino acids. Hydrophobic amino acid residues are predicted to group around each other, while hydrophilic residues interact with the surrounding water.
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Alternatively, steric or entropic repulsion is a phenomenon used to describe the repelling effect when adsorbed layers of material (such as polymer molecules swollen with solvent) are present on the surface of the pigment particles in dispersion. Only certain portions (anchors) of the polymer molecules are adsorbed, with their corresponding loops and tails extending out into the solution. As the particles approach each other their adsorbed layers become crowded; this provides an effective steric barrier that prevents flocculation. This crowding effect is accompanied by a decrease in entropy, whereby the number of conformations possible for the polymer molecules is reduced in the adsorbed layer.
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However, at lower resolutions (typically lower than 2.0Å), sequences/structures should either match known structures, or be supported by complementary techniques such as Mass Spectrometry. Also, monosaccharides have clear conformational preferences (saturated rings are typically found in chair conformations), but errors introduced during model building and/or refinement (wrong linkage chirality or distance, or wrong choice of model - see for recommendations on carbohydrate model building and refinement and for reviews on general errors in carbohydrate structures) can bring their atomic models out of their energy minima. Around 20% of the deposited carbohydrate structures are in unjustified energy minima. A number of carbohydrate validation web services are available at glycosciences.
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In order to change one conformation to the other, at some point those four atoms would have to lie on the same plane — which would require severely straining or breaking their bonds to the carbon atom. The corresponding energy barrier between the two conformations is so high that there is practically no conversion between them at room temperature, and they can be regarded as different configurations. The compound chlorofluoromethane , in contrast, is not chiral: the mirror image of its molecule is also obtained by a half-turn about a suitable axis. Another example of a chiral compound is 2,3-pentadiene –CH=C=CH– a hydrocarbon that contains two overlapping double bonds.
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The first successful x-ray crystal structure of an intact ABC importer is the molybdenum transporter (ModBC-A) from Archaeoglobus fulgidus. Atomic-resolution structures of three other bacterial importers, E. coli BtuCD, E. coli maltose transporter (MalFGK2-E), and the putative metal- chelate transporter of Haemophilus influenzae, HI1470/1, have also been determined. The structures provided detailed pictures of the interaction of the transmembrane and ABC domains as well as revealed two different conformations with an opening in two opposite directions. Another common feature of importers is that each NBD is bound to one TMD primarily through a short cytoplasmic helix of the TMD, the "coupling helix".
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For both apo conformations of MsbA, the chamber opening is facing inward. The structure of MsbA-AMP-PNP (5’-adenylyl-β-γ-imidodiphosphate), obtained from S. typhimurium, is similar to Sav1866. The NBDs in this nucleotide-bound, outward-facing conformation, come together to form a canonical ATP dimer sandwich, that is, the nucleotide is situated in between the P-loop and LSGGQ motif. The conformational transition from MsbA-closed-apo to MsbA-AMP-PNP involves two steps, which are more likely concerted: a ≈10° pivot of TM4/TM5 helices towards TM3/TM6, bringing the NBDs closer but not into alignment followed by tilting of TM4/TM5 helices ≈20° out of plane.
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Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), designed to be active against HIV with mutations that confer resistance to the two most commonly prescribed first-generation NNRTIs, mutation K103N for efavirenz and Y181C for nevirapine. This potency appears to be related to etravirine's flexibility as a molecule. Etravirine is a diarylpyrimidine (DAPY), a type of organic molecule with some conformational isomerism that can bind the enzyme reverse transcriptase in multiple conformations, allowing for a more robust interaction between etravirine and the enzyme, even in the presence of mutations. Other diarylpyrimidine- analogues are currently being used as anti-HIV agents, notably rilpivirine.
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In 1969, strong piezoelectricity was observed in PVDF, with the piezoelectric coefficient of poled (placed under a strong electric field to induce a net dipole moment) thin films as large as 6–7 pC/N: 10 times larger than that observed in any other polymer. PVDF has a glass transition temperature (Tg) of about −35 °C and is typically 50–60% crystalline. To give the material its piezoelectric properties, it is mechanically stretched to orient the molecular chains and then poled under tension. PVDF exists in several forms: alpha (TGTG'), beta (TTTT), and gamma (TTTGTTTG') phases, depending on the chain conformations as trans (T) or gauche (G) linkages.
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The equation aids in the elucidation of protein folding as well as the conformations of other rigid aliphatic molecules. The equilibrium between conformational isomers can be observed using a variety of spectroscopic techniques. In cyclohexane derivatives, the two chair conformers interconvert with rapidly at room temperature, with cyclohexane itself undergoing the ring- flip at a rates of approximately 105 ring-flips/sec, with an overall energy barrier of 10 kcal/mol (42 kJ/mol), which precludes their separation at ambient temperatures. However, at low temperatures below the coalescence point one can directly monitor the equilibrium by NMR spectroscopy and by dynamic, temperature dependent NMR spectroscopy the barrier interconversion.
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But there is reason to believe (e.g., neutron diffraction studies) that excluded volume effects may cancel out, so that, under certain conditions, chain dimensions in amorphous polymers have approximately the ideal, calculated size "Conformations, Solutions, and Molecular Weight" from "Polymer Science & Technology" courtesy of Prentice Hall Professional publications When separate chains interact cooperatively, as in forming crystalline regions in solid thermoplastics, a different mathematical approach must be used. Stiffer polymers such as helical polypeptides, Kevlar, and double-stranded DNA can be treated by the worm-like chain model. Even copolymers with monomers of unequal length will distribute in random coils if the subunits lack any specific interactions.
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Those RNA structures contain many stretches of A-form double helix, connected into definite 3D arrangements by single-stranded loops, bulges, and junctions. Examples are tRNA, ribosomes, ribozymes, and riboswitches. These complex structures are facilitated by the fact that RNA backbone has less local flexibility than DNA but a large set of distinct conformations, apparently because of both positive and negative interactions of the extra OH on the ribose. Structured RNA molecules can do highly specific binding of other molecules and can themselves be recognized specifically; in addition, they can perform enzymatic catalysis (when they are known as "ribozymes", as initially discovered by Tom Cech and colleagues).
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Enzymes are not rigid, static structures; instead they have complex internal dynamic motions – that is, movements of parts of the enzyme's structure such as individual amino acid residues, groups of residues forming a protein loop or unit of secondary structure, or even an entire protein domain. These motions give rise to a conformational ensemble of slightly different structures that interconvert with one another at equilibrium. Different states within this ensemble may be associated with different aspects of an enzyme's function. For example, different conformations of the enzyme dihydrofolate reductase are associated with the substrate binding, catalysis, cofactor release, and product release steps of the catalytic cycle, consistent with catalytic resonance theory.
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His most convincing work was done on the camphoraceous odor, for which he posited a hemispherical socket in which spherical molecules, such as camphor, cyclooctane, and naphthalene could bind. When Linda Buck and Richard Axel published their Nobel Prize winning research on the olfactory receptors in 1991, they identified in mice 1,000 G-protein-coupled receptors used for olfaction. Since all types of G-protein receptors currently known are activated through binding (docking) of molecules with highly specific conformations (shapes) and non-covalent interactions, it is assumed that olfactory receptors operate in a similar fashion. Further research on human olfaction systems identified 347 olfactory receptors.
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At higher temperatures, conversion between different conformations of unbound add adenine riboswitch favors the form that is able to accept adenine into its binding pocket. Higher temperatures also favor the conversion of this unbound riboswitch to the adenine-bound, start-sequence-exposed conformation. The concentration of Magnesium ion has an influence on only the latter of these conformation changes, and favors the binding of adenine to the riboswitch. The combination of these effects facilitates a more controlled translation of the add gene at lower temperatures: taking a portion of the unbound riboswitch and rendering it unable to bind adenine increases the sensitivity of the remaining portion to magnesium.
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Three of these were of the wild type: the apoenzyme in , the enzyme plus its magnesium ion cofactor in , and the enzyme at high ionic strength in . A mutant (D58A, in one of the active-site loops) was crystallized as an apoenzyme also (). From these structures, an active-site "gating" loop (residues 115-133) that shields the substrate from solvent in the closed conformation was identified. The two conformations, taken from the crystal structures 1M1B (closed) and 1S2T (open), are docked into each other in the images below; they differ negligibly except in the gating loop, which is colored purple for the closed conformation and blue for the open conformation.
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The folded state had a well-defined pi stacking interaction with a T-shaped geometry, whereas the unfolded state had no aryl–aryl interactions. The NMR chemical shifts of the two conformations were distinct and could be used to determine the ratio of the two states, which was interpreted as a measure of intramolecular forces. The authors report that a preference for the folded state is not unique to aryl esters. For example, the cyclohexyl ester favored the folded state more so than the phenyl ester, and the tert-butyl ester favored the folded state by a preference greater than that shown by any aryl ester.
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In general, the most accurate predictions are for loops of fewer than 8 amino acids. Extremely short loops of three residues can be determined from geometry alone, provided that the bond lengths and bond angles are specified. Slightly longer loops are often determined from a "spare parts" approach, in which loops of similar length are taken from known crystal structures and adapted to the geometry of the flanking segments. In some methods, the bond lengths and angles of the loop region are allowed to vary, in order to obtain a better fit; in other cases, the constraints of the flanking segments may be varied to find more "protein-like" loop conformations.
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In stereochemistry, the Klyne–Prelog system (named for William Klyne and Vladimir Prelog) for describing conformations about a single bond offers a more systematic means to unambiguously name complex structures, where the torsional or dihedral angles are not found to occur in 60° increments.Klyne, W & Prelog V. Description of steric relationships across single bonds. Experientia 16:521–23, 1960 Klyne notation views the placement of the substituent on the front atom as being in regions of space called anti/syn and clinal/periplanar relative to a reference group on the rear atom. A plus (+) or minus (–) sign is placed at the front to indicate the sign of the dihedral angle.
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LID domains have been found in other kinases, and these domains are regions which are able to move after substrate binding. They are responsible for coordination of three distinct conformations, an open state in the absence of substrate, a partially closed state after substrate binding, and a fully closed state when both substrates are present. In H. influenzae, NR enters the NAD+ resynthesis pathway after phosphorylation to NMN, and subsequently, NAD+ is synthesized from NMN and ATP via an NMN adenylyl transferase activity. NadR represents a multifunctional regulator/enzyme complex able to integrate several functions, such as enzymatic catalysis, transport, and transcriptional regulatory activities.
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The 3' splice site region used to produce M2 was experimentally probed with structure-sensitive chemicals and enzymes and was found to adopt both the hairpin and pseudoknot conformations in solution. Each conformation places important splicing regulatory sites in different structural environments, which has implications for the modulation of splicing of the segment 7 transcript. For example, the splice site, polypyrimidine tract, branch point, and ASF/SF2 exonic enhancer binding sites are expected to be more accessible in the hairpin conformation and less accessible in the pseudoknot (Figure 1). By shifting the equilibrium between the pseudoknot and hairpin it may be possible to reduce or enhance M2 splicing, respectively.
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Atomic force microscopy (AFM) is an excellent method for obtaining high spatial resolution images of membrane proteins, but it might not be helpful to investigate its binding kinetics. Fluorescence-based microscopy (FLM) can be used to study the interactions of membrane proteins in individual cells but it requires development of proper labels and needs tactics for different target proteins. Furthermore, host protein may be affected by the labeling. Binding kinetics of MP's in the single living cells can be studied via label free imaging method based on SPR Microscopy without extracting the proteins from the cell membranes, which help scientists to work with the actual conformations of the membrane proteins.
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Like all P-type ATPases, a phosphate group is transferred from adenosine triphosphate (ATP) to the H+/K+ ATPase during the transport cycle. This phosphate transfer powers a conformational change in the enzyme that helps drive ion transport. The hydrogen potassium ATPase is activated indirectly by gastrin that causes ECL cells to release histamine. The histamine binds to H2 receptors on the parietal cell, activating a cAMP- dependent pathway which causes the enzyme to move from the cytoplasmic tubular membranes to deeply folded canaliculi of the stimulated parietal cell. Once localized, the enzyme alternates between two conformations, E1 and E2, to transport ions across the membrane.
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In proliferating cells, certain Rb conformations (when RxL motif if bound by protein phosphatase 1 or when it is acetylated or methylated) are resistant to CDK phosphorylation and retain other function throughout cell cycle progression, suggesting not all Rb in the cell are devoted to guarding the G1/S transition. Studies have also demonstrated that hyperphosphorylated Rb can specifically bind E2F1 and form stable complexes throughout the cell cycle to carry out unique unexplored functions, a surprising contrast from the classical view of Rb releasing E2F factors upon phosphorylation. In summary, many new findings about Rb's resistance to CDK phosphorylation are emerging in Rb research and shedding light on novel roles of Rb beyond cell cycle regulation.
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Continued investigation of the various opened and closed, inactive and active conformations of KcsA by other imaging methods such as ssNMR and EPR have since provided even more insight into channel structure and the forces gating the switch from channel inactivation to conduction. In 2007, Riek et. Al. showed that the channel opening that results from titrating the ion channel from pH 7 to pH 4, corresponds to conformational changes in two regions: transition to the ion-exchanging state of the selectivity filter, and the opening of the arrangement of TM2 at the C-terminus. This model explains the ability of KcsA to simultaneous select for K+ ions while also gating electrical conductance.
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The mechanical properties of the tendon are dependent on the collagen fiber diameter and orientation. The collagen fibrils are parallel to each other and closely packed, but show a wave-like appearance due to planar undulations, or crimps, on a scale of several micrometers. In tendons, the collagen fibres have some flexibility due to the absence of hydroxyproline and proline residues at specific locations in the amino acid sequence, which allows the formation of other conformations such as bends or internal loops in the triple helix and results in the development of crimps. The crimps in the collagen fibrils allow the tendons to have some flexibility as well as a low compressive stiffness.
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In statistical thermodynamics, the symmetry number corrects for any overcounting of equivalent molecular conformations in the partition function. In this sense, the symmetry number depends upon how the partition function is formulated. For example, if one writes the partition function of ethane so that the integral includes full rotation of a methyl, then the 3-fold rotational symmetry of the methyl group contributes a factor of 3 to the symmetry number; but if one writes the partition function so that the integral includes only one rotational energy well of the methyl, then the methyl rotation does not contribute to the symmetry number. Symmetry Numbers for Rigid, Flexible and Fluxional Molecules: Theory and Applications.
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For example, in a protein redesign of one small amino acid (such as alanine) in the tightly packed core of a protein, very few mutants would be predicted by a rational design approach to fold to the target structure, if the surrounding side-chains are not allowed to be repacked. Thus, an essential parameter of any design process is the amount of flexibility allowed for both the side-chains and the backbone. In the simplest models, the protein backbone is kept rigid while some of the protein side-chains are allowed to change conformations. However, side-chains can have many degrees of freedom in their bond lengths, bond angles, and χ dihedral angles.
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By convention, a chain under 30 amino acids is often identified as a peptide, rather than a protein. To be able to perform their biological function, proteins fold into one or more specific spatial conformations driven by a number of non-covalent interactions such as hydrogen bonding, ionic interactions, Van der Waals forces, and hydrophobic packing. To understand the functions of proteins at a molecular level, it is often necessary to determine their three-dimensional structure. This is the topic of the scientific field of structural biology, which employs techniques such as X-ray crystallography, NMR spectroscopy, cryo electron microscopy (cryo-EM) and dual polarisation interferometry to determine the structure of proteins.
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A double bond between two carbon atoms forces the remaining four bonds (if they are single) to lie on the same plane, perpendicular to the plane of the bond as defined by its π orbital. If the two bonds on each carbon connect to different atoms, two distinct conformations are possible, that differ from each other by a twist of 180 degrees of one of the carbons about the double bond. The classical example is dichloroethene , specifically the structural isomer ClHC=CHCl that has one chlorine bonded to each carbon. It has two conformational isomers, with the two chlorines on the same side or on opposite sides of the double bond's plane.
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Therefore, one has different configurational isomers depending on whether each hydroxyl is on "this side" or "the other side" of the ring's mean plane. Discounting isomers that are equivalent under rotations, there are nine isomers that differ by this criterion, and behave as different stable substances (two of them being enantiomers of each other). The most common one in nature (myo-inositol) has the hydroxyls on carbons 1, 2, 3 and 5 on the same side of that plane, and can therefore be called cis-1,2,3,5-trans-4,6-cyclohexanehexol. And each of these cis-trans isomers can possibly have stable "chair" or "boat" conformations (although the barriers between these are significantly lower than those between different cis-trans isomers).
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350x350px The enzyme responsible for making isoarborinol may represent the evolutionary link between the hopanol-producing enzymes in bacteria and the sterol-producing enzymes in eukaryotes. These enzymes are part of the class of terpene cyclases, which cyclize either squalene or oxidosqualene into four- or five-membered ring compounds through pathways that proceed through different structural conformations (all-chair or chair-boat-chair). Each terpene cyclase uses a different combination of these aspects to produce the final polycyclic triterpenoid compound, leading to great variety in the pathways of polycyclic triterpenoid production. Squalene- hopene cyclase (SHC) synthesizes hopanols and is generally assumed to have evolved before the sterol-producing enzyme oxidosqualene cyclase (OSC).
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His work on medium-sized alicyclic and heterocyclic rings established him as a pioneer in stereochemistry and conformational theory and brought an invitation to give the first Centenary Lecture of the Chemical Society in London in 1949. He synthesised medium-sized ring compounds with 8 to 12 members from dicarboxylic acid esters by acyloin condensation and explained their unusual chemical reactivity by a "nonclassical" strain because of energetically unfavorable conformations. He also contributed to the understanding of Bredt's rule by showing that a double bond may occur at the bridgehead if the ring is large enough. In his research of asymmetric syntheses, Prelog studied enantioselective reactions and established rules for the relationship between configuration of educts and products.
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He was elected a member of the National Academy of Sciences in 1956. Newman received numerous awards, including the American Chemical Society (ACS) Award for Creative Work in Synthetic Organic Chemistry in 1961, the Morley Medal given by the Cleveland, Ohio section of the ACS in 1969, the Wilbur Lucius Cross Medal by Yale in 1975, an honorary doctorate by the University of New Orleans in 1975, the Columbus section of the ACS award in 1976, and the Joseph Sullivant Medal by Ohio State University in 1976. In addition, the Newman projection - which allows organic chemists to represent different conformations of molecules in space - was introduced by the chemist. Newman was an avid golfer.
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Factor H exerts its protective action on self cells and self surfaces but not on the surfaces of bacteria or viruses. This is thought to be the result of Factor H having the ability to adopt conformations with lower or higher activities as a cofactor for C3 cleavage or decay accelerating activity. The lower activity conformation is the predominant form in solution and is sufficient to control fluid phase amplification. The more active conformation is thought to be induced when Factor H binds to glycosaminoglycans (GAGs) and or sialic acids that are generally present on host cells but not, normally, on pathogen surfaces ensuring that self surfaces are protected whilst complement proceeds unabated on foreign surfaces.
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The term is useful when examining protein folding; while a protein can theoretically exist in a nearly infinite number of conformations along its energy landscape, in reality proteins fold (or "relax") into secondary and tertiary structures that possess the lowest possible free energy. The key concept in the energy landscape approach to protein folding is the folding funnel hypothesis. In catalysis, when designing new catalysts or refining existing ones, energy landscapes are considered to avoid low-energy or high- energy intermediates that could halt the reaction or demand excessive energy to reach the final products. In glassing models, the local minima of an energy landscape correspond to metastable low temperature states of a thermodynamic system.
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In molecular mechanics, several ways exist to define the environment surrounding a molecule or molecules of interest. A system can be simulated in vacuum (termed a gas-phase simulation) with no surrounding environment, but this is usually undesirable because it introduces artifacts in the molecular geometry, especially in charged molecules. Surface charges that would ordinarily interact with solvent molecules instead interact with each other, producing molecular conformations that are unlikely to be present in any other environment. The best way to solvate a system is to place explicit water molecules in the simulation box with the molecules of interest and treat the water molecules as interacting particles like those in the molecule.
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DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have been directly observed in functional organisms. The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution. The first published reports of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based on Patterson transforms that provided only a limited amount of structural information for oriented fibers of DNA. An alternative analysis was then proposed by Wilkins et al.
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Within the U2 snRNA, there are other mutually exclusive rearrangements that occur between competing conformations. For example, in the active form, stem loop IIa is favored; in the inactive form a mutually exclusive interaction between the loop and a downstream sequence predominates. It is unclear how U4 is displaced from U6 snRNA, although RNA has been implicated in spliceosome assembly, and may function to unwind U4/U6 and promote the formation of a U2/U6 snRNA interaction. The interactions of U4/U6 stem loops I and II dissociate and the freed stem loop II region of U6 folds on itself to form an intramolecular stem loop and U4 is no longer required in further spliceosome assembly.
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Thus, a voltage-gated ion channel tends to be open for some values of the membrane potential, and closed for others. In most cases, however, the relationship between membrane potential and channel state is probabilistic and involves a time delay. Ion channels switch between conformations at unpredictable times: The membrane potential determines the rate of transitions and the probability per unit time of each type of transition. Action potential propagation along an axon Voltage-gated ion channels are capable of producing action potentials because they can give rise to positive feedback loops: The membrane potential controls the state of the ion channels, but the state of the ion channels controls the membrane potential.
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A later proposal was that the GGUG motif is recognised by the zinc finger domain and not the RRM (80). Additionally, FUS/TLS has been found to bind a relatively long region in the 3′ untranslated region (UTR) of the actin- stabilising protein Nd1-L mRNA, suggesting that rather than recognising specific short sequences, FUS/TLS interacts with multiple RNA-binding motifs or recognises secondary conformations. FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro. Beyond nucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to influence the initiation of transcription.
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One inhibitor, dicholoroacetate (DCA), binds at the center of the R domain. Within the active site, there are three amino acid residues, R250, T302, and Y320, that make the kinase resistant to the inhibitor dichloroacetate, which uncouples the active site from the allosteric site. This supports the theory that R250, T302, and Y320 stabilize the "open" and "closed" conformations of the built-in lid that controls the access of a nucleotide into the nucleotide-binding cavity. This strongly suggests that the mobility of ATP lid is central to the allosteric regulation of PDHK2 activity serving as a conformational switch required for communication between the active site and allosteric sites in the kinase molecule.
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Loop modeling is a problem in protein structure prediction requiring the prediction of the conformations of loop regions in proteins with or without the use of a structural template. Computer programs that solve these problems have been used to research a broad range of scientific topics from ADP to breast cancer. Because protein function is determined by its shape and the physiochemical properties of its exposed surface, it is important to create an accurate model for protein/ligand interaction studies. The problem arises often in homology modeling, where the tertiary structure of an amino acid sequence is predicted based on a sequence alignment to a template, or a second sequence whose structure is known.
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This is due, in part, to the lower amount of information contained in data obtained by NMR. Because of this fact, it has become common practice to establish the quality of NMR ensembles, by comparing it against the unique conformation determined by X-ray diffraction, for the same protein. However, the X-ray diffraction structure may not exist, and, since the proteins in solution are flexible molecules, a protein represented by a single structure may lead to underestimate the intrinsic variation of the atomic positions of a protein. A set of conformations, determined by NMR or X-ray crystallography may be a better representation of the experimental data of a protein than a unique conformation.
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Proposed binding site interactions of substance 14 One Italian research group discovered through digital screening that commercially available thiadiazole derivatives displayed moderate inhibitory action on both Abl and Src kinases. Using a 1,3,4 thiadiazol core and trying different groups or molecules on the benzene rings, several different substances with inhibitory properties were produced. The flexibility of the core allowed a number of conformations of the substances to bind to the ATP site of the Abl kinase, though all of them bound to the kinase's active form. Further study of the binding showed that the position of the sulfur that binds to the toluene structure played an important role in regard to Abl binding and also that only one of the nitrogen's one thiadiazole formed a hydrogen bond.
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SSCP used to be a way to discover new DNA polymorphisms apart from DNA sequencing but is now being supplanted by sequencing techniques on account of efficiency and accuracy. These days, SSCP is most applicable as a diagnostic tool in molecular biology. It can be used in genotyping to detect homozygous individuals of different allelic states, as well as heterozygous individuals that should each demonstrate distinct patterns in an electrophoresis experiment. SSCP is also widely used in virology to detect variations in different strains of a virus, the idea being that a particular virus particle present in both strains will have undergone changes due to mutation, and that these changes will cause the two particles to assume different conformations and, thus, be differentiable on an SSCP gel.
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While the sequence of SVV's protein-coding genome is most similar to members in the Cardiovirus genus, the non-coding RNA internal ribosome entry site (IRES) is most similar to those of the Pestivirus genus, including classical swine fever virus, and Hepacivirus genus, including Hepatitis C virus. The SVV IRES RNA shares similarities in sequence, structure, and function with the hepatitis C virus IRES. Subdomain IIa of the SVV and HCV IRES shares a similar structure and ligand-binding function as seen in its crystal structure. This subdomain IIa region is classified as a ligand-responsive RNA switch which adopts well- defined ligand-free and bound conformations without breaking or forming any base pairs in its secondary structure upon interconversion between the two states.
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Moreover, all available crystal structures of complexes between YARS and tRNA(Tyr) are also planar, with symmetrical conformations of the two monomers in the dimer and with two tRNA(Tyr) molecules simultaneously interacting with one YARS dimer. However, kinetic studies of tyrosine activation and tRNA(Tyr) charging have revealed an anticooperative behavior of the TyrRS dimer in solution: each TyrRS dimer binds and tyrosylates only one tRNA(Tyr) molecule at a time. Thus, only one of the two sites is active at any given time. The presence of base pair Gua1:Cyt72 in the acceptor stem of tRNA(Tyr) from eubacteria and of base pair Cyt1-Gua72 in tRNA(Tyr) from archaea and eukaryotes results in a species specific recognition of tRNATyr by tyrosyl-tRNA synthetase.
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The two possible stacked forms differ in which pairs of the arms are stacked with each other; which of the two dominates is highly dependent on the base sequences nearest to the junction. Some sequences result in an equilibrium between the two conformers, while others strongly prefer a single conformer. In particular, junctions containing the sequence A-CC bridging the junction point appear to strongly prefer the conformer that allows a hydrogen bond to form between the second cytosine and one of the phosphates at the junction point. While most studies have focused on the identities of the four bases nearest to the junction on each arm, it is evident that bases farther out can also affect the observed stacking conformations.
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The 6-vertex edge ring does not conform to the shape of a perfect hexagon. The conformation of a flat 2D planar hexagon has considerable angle strain because its bonds are not 109.5 degrees; the torsional strain would also be considerable because all of the bonds would be eclipsed bonds. Therefore, to reduce torsional strain, cyclohexane adopts a three-dimensional structure known as the chair conformation, which rapidly interconvert at room temperature via a process known as a chair flip. During the chair flip, there are three other intermediate conformations that are encountered: the half- chair, which is the most unstable conformation, the more stable boat conformation, and the twist-boat, which is more stable than the boat but still much less stable than the chair.
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Overall, the free energy of steric interactions (ΔGs) can be expressed as a function of both elastic repulsive energy (ΔGel) and the free energy of mixing (ΔGmix): ΔGs = ΔGel \+ ΔGmix The elastic repulsive energy (ΔGel), increases as more polymers adsorb to the surfaces of clay particles. This can be modeled as: ΔGel = 2kBTΓln(Ω(h)/Ω(∞)) where kB is the Boltzmann constant, T is the temperature, Γ is the number of adsorbed polymers per unit surface area, and Ω(h) and Ω(∞) are the number of available conformations at h and infinite distances. ΔGs due to steric interactions is also a function of the free energy of mixing (ΔGmix). Most commonly, this will favor greater distances between polymer molecules in solution.
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Perfect convergence for the SCMF method would result in a probability of 1 for exactly one rotamer at each position k in the protein, and a probability of zero for all other rotamers at each position. Convergence to a unique solution requires probabilities close to 1 for exactly one rotamer at each position. In practice, especially when higher temperatures are used, the algorithm instead identifies a small number of high-probability rotamers at each position, allowing the resulting conformations' relative energies to then be enumerated (based on the precomputed energies, not on those derived from the mean-field approximation). One way to improve convergence is to run again at a lower temperature using the probabilities calculated from a previous higher-temperature run.
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It has been suggested that the mannose receptor can exist in at least two different structural conformations. The C-type CRDs are each separated by linker regions of 10-20 amino acids containing a number of proline residues, whose cyclic side chain is fairly rigid and favours a conformation in which the N-terminal cysteine- rich domain is extended as far away from the plasma membrane as possible. Alternatively, interactions between neighbouring CRDs may hold them in close proximity to one another and cause the extracellular region of the receptor to bend, bringing the N-terminal cysteine-rich domain into close contact with the CRDs. This would position CRDs 4 and 5 furthest from the membrane to maximise their interaction with potential ligands.
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The Senate of Costa Rica was the upper chamber of the Costa Rican Legislative branch as prescribed in the constitutions of 1844, 1859, 1869 and 1917. During all these different constitutions, the Senate had different characteristics and conformations. The Constitution of 1844 established a House of Senators of five senators and their alternates who was renewed by thirds on an annual basis with the possibility of re-election. In the 1859 senators were ten per province that could be re-elected indefinitely and that was renewed every two years. This model was very similar to the Senate of the 1869 Constitution which established 11 senators by province elected for three years and one elected by the Comarca of Puntarenas (which was not yet a province).
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GABA is a very common neurotransmitter used in IPSPs in the adult mammalian brain and retina. GABA receptors are pentamers most commonly composed of three different subunits (α, β, γ), although several other subunits (δ,ε, θ, π, ρ) and conformations exist. The open channels are selectively permeable to chloride or potassium ions (depending on the type of receptor) and allow these ions to pass through the membrane. If the electrochemical potential of the ion is more negative than that of the action potential threshold then the resultant conductance change that occurs due to the binding of GABA to its receptors keeps the postsynaptic potential more negative than the threshold and decreases the probability of the postsynaptic neuron completing an action potential.
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The enzyme 4-hydroxybenzoate 3-monooxygenase, also commonly referred to as para-hydroxybenzoate hydroxylase (PHBH), is a flavoprotein belonging to the family of oxidoreductases. Specifically, it is a hydroxylase, and is one of the most studied enzymes and catalyzes reactions involved in soil detoxification, metabolism, and other biosynthetic processes. 4-hydroxybenzoate 3-monooygenase catalyzes the regioselective hydroxylation of 4-hydroxybenzoate, giving 3,4-dihydroxybenzoate as the product. The mechanism consists of the following general steps: (1) reduction of the flavin, (2) reaction of the flavin with O2, producing C4a-hydroperoxyflavin, and (3) binding and activation of the substrate, leading to product formation and release. Throughout the mechanism, the flavin changes between “open” and “closed” conformations, thus altering the substrate reaction environment.
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At Madras University, Professor Ramachandran was the favourite of the famous vice-chancellor and celebrated doctor and medical scientist, Sir Arcot Laksmanaswamy Mudaliar. Wanting to tackle problems at a more fundamental level, Ramachandran decided to use this information to examine the various polypeptide conformations then known and also to develop a good 'yardstick' that could be used for examining and assessing any structure in general, but peptides in particular. The result which emerged from these calculations in 1962, – now commonly known as the Ramachandran plot – was published in the Journal of Molecular Biology in 1963 and has become an essential tool in the field of protein conformation. When it was first calculated, crystal structures had barely been obtained for any protein.
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One groove, the major groove, is 22 angstroms (Å) wide and the other, the minor groove, is 12 Å wide. The width of the major groove means that the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove. This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.
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In glycolysis, hexokinase is directly inhibited by its product, glucose-6-phosphate, and pyruvate kinase is inhibited by ATP itself. The main control point for the glycolytic pathway is phosphofructokinase (PFK), which is allosterically inhibited by high concentrations of ATP and activated by high concentrations of AMP. The inhibition of PFK by ATP is unusual, since ATP is also a substrate in the reaction catalyzed by PFK; the active form of the enzyme is a tetramer that exists in two conformations, only one of which binds the second substrate fructose-6-phosphate (F6P). The protein has two binding sites for ATP – the active site is accessible in either protein conformation, but ATP binding to the inhibitor site stabilizes the conformation that binds F6P poorly.
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The PDGFRB gene encodes a typical receptor tyrosine kinase, which belongs to the type III tyrosine kinase receptor (RTK) family and is structurally characterized by five extracellular immunoglobulin-like domains, a single membrane-spanning helix domain, an intracellular juxtamembrane domain, a split tyrosine kinase domain and a carboxylic tail. In the absence of ligand, PDGFRβ adopts an inactive conformation in which the activation loop folds over the catalytic site, the juxtamembrane region over a loop occluding the active site and the carboxy- terminal tail over the kinase domain. Upon PDGF binding the dimerization of receptor releases the inhibitory conformations due to auto-phosphorylation of regulatory tyrosine residues in trans fashion. Tyrosine residues 857 and 751 are major phosphorylation sites for the activation of PDGFRβ.
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A low (negative) energy indicates a stable system and thus a likely binding interaction. An alternative approach is to derive a knowledge-based statistical potential for interactions from a large database of protein-ligand complexes, such as the Protein Data Bank, and evaluate the fit of the pose according to this inferred potential. There are a large number of structures from X-ray crystallography for complexes between proteins and high affinity ligands, but comparatively fewer for low affinity ligands as the later complexes tend to be less stable and therefore more difficult to crystallize. Scoring functions trained with this data can dock high affinity ligands correctly, but they will also give plausible docked conformations for ligands that do not bind.
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Since the early 1990s, scientists started to study how the group I intron achieves its native structure in vitro, and some mechanisms of RNA folding have been appreciated thus far. It is agreed that the tertiary structure is folded after the formation of the secondary structure. During folding, RNA molecules are rapidly populated into different folding intermediates, the intermediates containing native interactions are further folded into the native structure through a fast folding pathway, while those containing non-native interactions are trapped in metastable or stable non-native conformations, and the process of conversion to the native structure occurs very slowly. It is evident that group I introns differing in the set of peripheral elements display different potentials in entering the fast folding pathway.
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Affimer proteins were developed initially at the MRC Cancer Cell Unit in Cambridge then across two laboratories at the University of Leeds. Derived from the cysteine protease inhibitor family of cystatins, which function in nature as cysteine protease inhibitors, these 12–14 kDa proteins share the common tertiary structure of an alpha-helix lying on top of an anti-parallel beta-sheet. Affimer proteins display two peptide loops and an N-terminal sequence that can all be randomised to bind to desired target proteins with high affinity and specificity, in a similar manner to monoclonal antibodies. Stabilisation of the two peptides by the protein scaffold constrains the possible conformations that the peptides can take, increasing the binding affinity and specificity compared to libraries of free peptides.
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Decadienoic acids with the two double bonds in the same positions can be further distinguished by the geometry of the adjacent single bonds. Each double bond that is adjacent to two single C–C bonds can be in two cis-trans conformations, namely with those two single bonds on the same side (cis or Z) or opposite sides (trans or E) of the double bond's plane. If the two double bonds overlap forming an allene core C=C=C surrounded by two single C–C bonds, the chain fragments C–C=C=C and C=C=C–C will lie on perpendicular planes. Then, instead of cis-trans isomers, there will be two axial isomers distinguished by the handedness of the C–C=C=C–C "screw".
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He is known for his foundational work in three-dimensional protein and nucleic acid structure determination by biomolecular NMR spectroscopy, for advancing experimental approaches to the study of large macromolecules and their complexes by NMR, and for developing NMR-based methods to study rare conformational states in protein-nucleic acid and protein-protein recognition. Clore's discovery of previously undetectable, functionally significant, rare transient states of macromolecules has yielded fundamental new insights into the mechanisms of important biological processes, and in particular the significance of weak interactions and the mechanisms whereby the opposing constraints of speed and specificity are optimized. Further, Clore's work opens up a new era of pharmacology and drug design as it is now possible to target structures and conformations that have been heretofore unseen.
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Gautham used DNA Crystallography to study the impact of metal ions on the transition of right-handed B-DNA to left-handed Z-DNA. as well as the self assembly of DNA decameric sequences into a four-way Holliday junction In the area of structural bioinformatics, Gautham developed a novel Ab initio computational method using Mutually Orthogonal Latin squares (MOLS) - a technique employed in the area of experimental design - to efficiently sample the conformational space of polypeptides and proteins in order to identify global minimum energy conformations. Later, his laboratory applied the MOLS technique to the problem of molecular docking and produced an open source software package called MOLS. Gautham has written two textbooks in the field of Biophysics and Bioinformatics.
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Typically, the optimal alignment (a translation and an in-plane rotation) to map one image onto another is calculated by cross-correlation. However, a micrograph often contains particles in multiple different orientations and/or conformations, and so to get more representative image averages, a method is required to group similar particle images together into multiple sets. This is normally carried out using one of several data analysis and image classification algorithms, such as multi-variate statistical analysis and hierarchical ascendant classification, or k-means clustering. Often data sets of tens of thousands of particle images are used, and to reach an optimal solution an iterative procedure of alignment and classification is used, whereby strong image averages produced by classification are used as reference images for a subsequent alignment of the whole data set.
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The simplicity of the hydrophobic-polar model has caused it to have several problems that people have attempted to correct with alternative lattice protein models. Chief among these problems is the issue of degeneracy, which is when there is more than one minimum energy conformation for the modeled protein, leading to uncertainty about which conformation is the native one. Attempts to address this include the HPNX model which classifies amino acids as hydrophobic (H), positive (P), negative (N), or neutral (X) according to the charge of the amino acid, adding additional parameters to reduce the number of low energy conformations and allowing for more realistic protein simulations. Another model is the Crippen model which uses protein characteristics taken from crystal structures to inform the choice of native conformation.
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Purified RNase V1 is a commonly used reagent in molecular biology experiments. In conjunction with other ribonucleases that cleave single-stranded RNA after specific nucleotides or sequences – such as RNase T1 and RNase I – it can be used to map internal interactions in large RNA molecules with complex secondary structure or to perform footprinting experiments on macromolecular complexes containing RNA. RNase V1 is the only commonly used laboratory RNase that provides positive evidence for the presence of double-stranded helical conformations in target RNA. Because RNase V1 has some activity against RNA that is base-paired but single-stranded, dual susceptibility to both RNase V1 and RNase I at a single site in a target RNA molecule provides evidence of this relatively unusual conformation found in RNA loops.
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The first published reports for DNA (by Rosalind Franklin and Raymond Gosling in 1953) of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based on Patterson function transforms that provided only a limited amount of structural information for oriented fibers of DNA isolated from calf thymus. An alternate analysis was then proposed by Wilkins et al. in 1953 for B-DNA X-ray diffraction and scattering patterns of hydrated, bacterial-oriented DNA fibers and trout sperm heads in terms of squares of Bessel functions. Although the B-DNA form' is most common under the conditions found in cells, it is not a well-defined conformation but a family or fuzzy set of DNA conformations that occur at the high hydration levels present in a wide variety of living cells.
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However, in general and perhaps surprisingly, when branching is not extensive enough to make highly disfavorable 1,2- and 1,3-alkyl–alkyl steric interactions (worth ~3.1 kcal/mol and ~3.7 kcal/mol in the case of the eclipsing conformations of butane and pentane, respectively) unavoidable, the branched alkanes are actually more thermodynamically stable than their linear (or less branched) isomers. For example, the highly branched 2,2,3,3-tetramethylbutane is about 1.9 kcal/mol more stable than its linear isomer, n-octane. Due to the subtlety of this effect, the exact reasons for this rule have been vigorously debated in the chemical literature and is yet unsettled. Several explanations, including stabilization of branched alkanes by electron correlation, destabilization of linear alkanes by steric repulsion, stabilization by neutral hyperconjugation, and/or electrostatic effects have been advanced as possibilities.
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Such varying molecular geometries can also be computed, at least in principle, by employing ab initio quantum chemistry methods that can attain high accuracy for small molecules, although claims that acceptable accuracy can be also achieved for polynuclelotides, and DNA conformations, were recently made on the basis of vibrational circular dichroism (VCD) spectral data. Such quantum geometries define an important class of ab initio molecular models of DNA which exploration has barely started, especially related to results obtained by VCD in solutions. More detailed comparisons with such ab initio quantum computations are in principle obtainable through 2D-FT NMR spectroscopy and relaxation studies of polynucleotide solutions or specifically labeled DNA, as for example with deuterium labels. In an interesting twist of roles, the DNA molecule was proposed to be used for quantum computing via DNA.
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All forms of protein structure summarized Folding is a spontaneous process that is mainly guided by hydrophobic interactions, formation of intramolecular hydrogen bonds, van der Waals forces, and it is opposed by conformational entropy. The process of folding often begins co-translationally, so that the N-terminus of the protein begins to fold while the C-terminal portion of the protein is still being synthesized by the ribosome; however, a protein molecule may fold spontaneously during or after biosynthesis. While these macromolecules may be regarded as "folding themselves", the process also depends on the solvent (water or lipid bilayer), the concentration of salts, the pH, the temperature, the possible presence of cofactors and of molecular chaperones. Proteins will have limitations on their folding abilities by the restricted bending angles or conformations that are possible.
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Example of a small eukaryotic heat shock protein Molecular chaperones are a class of proteins that aid in the correct folding of other proteins in vivo. Chaperones exist in all cellular compartments and interact with the polypeptide chain in order to allow the native three-dimensional conformation of the protein to form; however, chaperones themselves are not included in the final structure of the protein they are assisting in. Chaperones may assist in folding even when the nascent polypeptide is being synthesized by the ribosome. Molecular chaperones operate by binding to stabilize an otherwise unstable structure of a protein in its folding pathway, but chaperones do not contain the necessary information to know the correct native structure of the protein they are aiding; rather, chaperones work by preventing incorrect folding conformations.
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This means that if one pathway is found to be more thermodynamically favorable than another, it is likely to be used more frequently in the pursuit of the native structure. As the protein begins to fold and assume its various conformations, it always seeks a more thermodynamically favorable structure than before and thus continues through the energy funnel. Formation of secondary structures is a strong indication of increased stability within the protein, and only one combination of secondary structures assumed by the polypeptide backbone will have the lowest energy and therefore be present in the native state of the protein. Among the first structures to form once the polypeptide begins to fold are alpha helices and beta turns, where alpha helices can form in as little as 100 nanoseconds and beta turns in 1 microsecond.
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In theory, the heteronuclear single quantum correlation has one peak for each H bound to a heteronucleus. Thus, in the 15N-HSQC, with a 15N labelled protein, one signal is expected for each nitrogen atom in the back bone, with the exception of proline, which has no amide-hydrogen due to the cyclic nature of its backbone. Additional 15N-HSQC signals are contributed by each residue with a nitrogen- hydrogen bond in its side chain (W, N, Q, R, H, K). The 15N-HSQC is often referred to as the fingerprint of a protein because each protein has a unique pattern of signal positions. Analysis of the 15N-HSQC allows researchers to evaluate whether the expected number of peaks is present and thus to identify possible problems due to multiple conformations or sample heterogeneity.
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Which of the possible chair conformations predominate in cyclohexanes bearing one or more substituents depends on the substiuents, and where they are located on the ring; generally, "bulky" substituents—those groups with large volumes, or groups that are otherwise repulsive in their interactions—prefer to occupy an equatorial location. An example of interactions within a molecule that would lead to steric strain, leading to a shift in equilibrium from boat to chair, is the interaction between the two methyl groups in cis-1,4-dimethylcyclohexane. In this molecule, the two methyl groups are in opposing positions of the ring (1,4-), and their cis stereochemistry projects both of these groups toward the same side of the ring. Hence, if forced into the higher energy boat form, these methyl groups are in steric contact, repel one another, and drive the equilibrium toward the chair conformation.
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In the alpha sheet, unlike other conformations, the peptide bonds are oriented in parallel so that the dipoles of the individual bonds can add up to create a strong overall electrostatic dipole. Notably, the protein lysozyme is among the few native-state proteins shown to contain an alpha-strand region; lysozyme from both chickens and humans contains an alpha strand located close to the site of a mutation known to cause hereditary amyloidosis in humans, usually an autosomal dominant genetic disease. Molecular dynamics simulations of the mutant protein reveal that the region around the mutation assumes an alpha strand conformation. Lysozyme is among the naturally occurring proteins known to form amyloid fibers under experimental conditions, and both natively alpha-strand region and the mutation site fall within the larger region identified as the core of lysozyme amyloid fibrillogenesis.
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Research on quasispecies has proceeded through several theoretical and experimental avenues that include continuing studies on evolutionary optimization and the origin of life, RNA-RNA interactions and replicator networks, the error threshold in variable fitness landscapes, consideration of chemical mutagenesis and proofreading mechanisms, evolution of tumor cells, bacterial populations or stem cells, chromosomal instability, drug resistance, and conformation distributions in prions (a class of proteins with conformation-dependent pathogenic potential; in this case the quasispecies is defined by a distribution of conformations). New inputs into experimental quasispecies research have come from deep sequencing to probe viral and cellular populations, recognition of interactions within mutant spectra, models of viral population dynamics related to disease progression and pathogen transmission, and new teachings from fidelity variants of viruses. Here we summarize the main aspects of quasispecies dynamics, and recent developments relevant to virus evolution and pathogenesis.
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Selectins have hinge domains, allowing them to undergo rapid conformational changes in the nanosecond range between ‘open’ and ‘closed’ conformations. Shear stress on the selectin molecule causes it to favor the ‘open’ conformation. In leukocyte rolling, the ‘open’ conformation of the selectin allows it to bind to inward sialyl Lewis molecules farther up along the PSGL-1 chain, increasing overall binding affinity—if the selectin-sialyl Lewis bond breaks, it can slide and form new bonds with the other sialyl Lewis molecules down the chain. In the ‘closed’ conformation, however, the selectin is only able to bind to one sialyl Lewis molecule, and thus has greatly reduced binding affinity. The result of such is that selectins exhibit catch and slip bond behavior—under low shear stresses, their bonding affinities are actually increased by an increase in tensile force applied to the bond because of more selectins preferring the ‘open’ conformation.
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The types of NMR usually done with nucleic acids are 1H or proton NMR, 13C NMR, 15N NMR, and 31P NMR. Two-dimensional NMR methods are almost always used, such as correlation spectroscopy (COSY) and total coherence transfer spectroscopy (TOCSY) to detect through-bond nuclear couplings, and nuclear Overhauser effect spectroscopy (NOESY) to detect couplings between nuclei that are close to each other in space. Parameters taken from the spectrum, mainly NOESY cross-peaks and coupling constants, can be used to determine local structural features such as glycosidic bond angles, dihedral angles (using the Karplus equation), and sugar pucker conformations. For large-scale structure, these local parameters must be supplemented with other structural assumptions or models, because errors add up as the double helix is traversed, and unlike with proteins, the double helix does not have a compact interior and does not fold back upon itself.
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The types of NMR usually done with nucleic acids are 1H or proton NMR, 13C NMR, 15N NMR, and 31P NMR. Two-dimensional NMR methods are almost always used, such as correlation spectroscopy (COSY) and total coherence transfer spectroscopy (TOCSY) to detect through-bond nuclear couplings, and nuclear Overhauser effect spectroscopy (NOESY) to detect couplings between nuclei that are close to each other in space. Parameters taken from the spectrum, mainly NOESY cross-peaks and coupling constants, can be used to determine local structural features such as glycosidic bond angles, dihedral angles (using the Karplus equation), and sugar pucker conformations. For large-scale structure, these local parameters must be supplemented with other structural assumptions or models, because errors add up as the double helix is traversed, and unlike with proteins, the double helix does not have a compact interior and does not fold back upon itself.
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This broad area represents the natural corridor that the Sierra Madre Occidental offered to the Toltec and Nahuatlaca tribes, both of whom took advantage of the large accidental stone conformations to survive in the wilderness of the territory. The new formations formed as the only security for the tribes that moved among Northern Mexico and the Valley of Anahuac, eventually becoming a home-state for these tribes who then began to form small communities, united by language and region. The Huichol, Cora, and Tarahumara Tepehuanos incorporated perfectly distinct nations, each with evident sedentary purposes, and a strong family structure, all whilst setting aside the bellicose attitude of the Chichimec tribe of the center of the then- current Republic. The exceptions were the Acaxee, Humas, and Xiximes who were constantly at war but always on the look-out for final settlements in the region of the Quebradas.
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The most basic possible comparison between protein structures makes no attempt to align the input structures and requires a precalculated alignment as input to determine which of the residues in the sequence are intended to be considered in the RMSD calculation. Structural superposition is commonly used to compare multiple conformations of the same protein (in which case no alignment is necessary, since the sequences are the same) and to evaluate the quality of alignments produced using only sequence information between two or more sequences whose structures are known. This method traditionally uses a simple least-squares fitting algorithm, in which the optimal rotations and translations are found by minimizing the sum of the squared distances among all structures in the superposition. More recently, maximum likelihood and Bayesian methods have greatly increased the accuracy of the estimated rotations, translations, and covariance matrices for the superposition.
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Crotamine has similar structural fold conformations to the human b-defensin family as well as identical disulfide bridges arrangement. [Figure needed] The gene and chromosome location responsible for its synthesis have been identified by the group led by Gandhi Rádis-Baptista, working at the Instituto Butantan, in São Paulo, Brazil. The mRNA has about 340 nucleotides and codifies a pre-crotamine, including the signal peptide, the mature crotamine, and a final lysine. The Crotamine gene was the first gene to be mapped on a snake chromosome. The gene responsible for coding the crotamine protein is labeled as Crt-p1 and its base pair sequence length is about 1.1kbp or 1100 bp. It was reported that the crotamine gene was isolated twice from two different specimens, one in a method that resulted in a gene size of 1.8 kbp and in the other specimen a gene size of 1.1 kbp.
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In concert with larger databases of known protein structures and modern machine learning methods such as neural nets and support vector machines, these methods can achieve up to 80% overall accuracy in globular proteins. The theoretical upper limit of accuracy is around 90%, partly due to idiosyncrasies in DSSP assignment near the ends of secondary structures, where local conformations vary under native conditions but may be forced to assume a single conformation in crystals due to packing constraints. Limitations are also imposed by secondary structure prediction's inability to account for tertiary structure; for example, a sequence predicted as a likely helix may still be able to adopt a beta-strand conformation if it is located within a beta-sheet region of the protein and its side chains pack well with their neighbors. Dramatic conformational changes related to the protein's function or environment can also alter local secondary structure.
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In an autobiographical piece, Richards wrote that "this discovery came as a surprise to the scientific community at that time.... In retrospect, this may have been the high point of my career in terms of excitement." This experiment showed that proteins maintain 3-dimensional order and tight binding between their interacting parts and that the structural information is inherent in the protein itself, foreshadowing both Anfinsen's later work showing that sequence determines structure and also the idea that hormones or other small molecules can bind tightly and specifically to proteins, a concept basic to how pharmaceutical companies design drugs today. Two years later, the protein structure of myoglobin confirmed such specific 3D relationships. Later, with Marilyn Doscher and Flo Quiocho, Richards demonstrated that ribonuclease S as well as carboxypeptidase were enzymatically active in the crystals, important evidence to silence doubts that the conformations of proteins in crystals are directly relevant to their biological activity in cells.
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The first step of SELEX involves the synthesis of fully or partially randomized oligonucleotide sequences of some length flanked by defined regions which allow PCR amplification of those randomized regions and, in the case of RNA SELEX, in vitro transcription of the randomized sequence. While Ellington and Szostak demonstrated that chemical synthesis is capable of generating ~1015 unique sequences for oligonucleotide libraries in their 1990 paper on in vitro selection, they found that amplification of these synthesized oligonucleotides led to significant loss of pool diversity due to PCR bias and defects in synthesized fragments. The oligonucleotide pool is amplified and a sufficient amount of the initial library is added to the reaction so that there are numerous copies of each individual sequence to minimize the loss of potential binding sequences due to stochastic events. Before the library is introduced to target for incubation and selective retention, the sequence library must be converted to single stranded oligonucleotides to achieve structural conformations with target binding properties.
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If fluorescence is detected when the fusion proteins are expressed, but is lacking or significantly reduced after the expression of the mutated negative control, it is likely that a specific interaction occurs between the two target proteins of interest. However, if the fluorescence intensity is not significantly different between the mutated negative control fusion protein and its wild-type counterpart, then the fluorescence is likely caused by non- specific protein interactions, so a different combination of fusion protein conformations should be tested. If no fluorescence is detected, an interaction may still exist between the proteins of interest, as the creation of the fusion protein may alter the structure or interaction face of the target protein or the fluorescence fragments may be physically unable to associate. To ensure that this result is not a false negative, that there is no interaction, the protein interaction must be tested in a situation where fluorescence complementation and activation requires an external signal.
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His primary focus, however, has been on quenched randomness in condensed matter and on stochastic processes in both irreversible and extended systems. His research on these topics was cited by the American Association for the Advancement of Science as "pioneering work on the statistical mechanics of disordered and noisy systems". He is best known for work on hierarchical dynamics (in collaboration with Elihu Abrahams, Philip Warren Anderson, and Richard Palmer); for observing that protein fluctuational conformations can be modeled using spin glass techniques; for constructing a theory of fluctuation-driven transitions in the absence of detailed balance (in collaboration with Robert Maier); for applying stochastic methods to determine lifetimes, stability, and decay of nanowires and nanomagnets (with a variety of collaborators); and for a series of rigorous and analytical results (largely with Charles M. Newman) on short- range spin glasses, including the introduction of the Newman-Stein metastate as a general mathematical tool for analyzing the thermodynamic properties of disordered systems.
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Cellular functions can be indirectly regulated by CaM, as it acts as a mediator for enzymes that require Ca2+ stimulation for activation. Studies have proven that calmodulin's affinity for Ca2+ increases when it is bound to a calmodulin-binding protein, which allows for it to take on its regulatory role for Ca2+-dependent reactions. Calmodulin, made up of 2 pairs of Ef-hand calcium binding domain 2 separated in different structural regions by an extended alpha helical region, that permits it to respond to the changes in the cytosolic concentration of the Ca2+ ions by taking on two distinct conformations, in the inactive Ca2+ unbound state and active Ca2+ bound state. Calmodulin binds to the targeted proteins via their short complementary peptide sequences, causing a “induced fit” conformational change that alters the calmodulin-binding proteins’ activity as desired in response to the second messenger Ca2+ signals that arise due to changes in the intracellular Ca2+ concentrations.
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A strong advocate of the combination of research and teaching, he has won a number of teaching awards, including the James Flack Norris Award of the American Chemical Society (1987), the E. Leroy Hall Award of the College of Arts and Sciences of Northwestern University (1991), the National Catalyst Award of the Chemical Manufacturers Association (1993), and the Northwestern University Alumni Award (1994). From 1999 to 2002 he was Charles Deering McCormick Professor of Teaching Excellence at Northwestern.Northwestern University 1999 Recipients of the McCormick and Alumnae Teaching Professorships His major scientific contributions include the creation of the first silyl cation (the silicon analogue of the carbocation), elucidation of the mechanism of beta-silyl stabilization of carbocations, discovery of inductive enhancement of solvolytic participation, creation of new methods of conformational analysis by nuclear magnetic resonance spectroscopy (the R value), understanding the conformations of cyclic molecules containing heteroatoms, and development of chemical methods to examine archaeological materials.
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The molecular and chemical composition of the organic or biological structure would represent not only the physical structure of the wetware but also the software, being continually reprogrammed by the discrete shifts in electrical pulses and chemical concentration gradients as the molecules change their structures to communicate signals. The responsiveness of a cell, proteins, and molecules to changing conformations, both within their own structures and around them, tie the idea of internal programming and external structure together in a way which is alien to the current model of conventional computer architecture. The structure of wetware represents a model where the external structure and internal programming are interdependent and unified; meaning that changes to the programming or internal communication between molecules of the device would represent a physical change in the structure. The dynamic nature of wetware borrows from the function of complex cellular structures in biological organisms. The combination of “hardware” and “software” into one dynamic, and interdependent system which utilizes organic molecules and complexes to create an unconventional model for computational devices is a specific example of applied biorobotics.
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CEF scientists in collaboration with the Max Planck Institute for Biophysical Chemistry visualized the RNA Polymerase I (Pol I) in the process of actively transcribing ribosome genes in a cellular environment and solved its structure with and without nucleic acids at 3.8 Å resolution by cryo-EM. Their structures explained the regulation of transcription elongation in which contracted and expanded polymerase conformations are associated with active and inactive states, respectively. Work by a collaboration between several CEF groups unravelled the molecular nature of Bowen-Conradi syndrome by demonstrating that the disease-causing point mutation of the ribosome biogenesis factor Nep1 impairs its nucleolar localisation and RNA binding. Another study, in collaboration with Edinburg University, analysed the RNA helicase Prp43 by crosslinking of RNA and analysis of cDNA (CRAC) and provided first insights into the functional roles of this enzyme in ribosome biogenesis CEF scientists also identified plant- specific ribosome biogenesis factors in A. thaliana with essential function in rRNA processing and showed that the 60S-associated ribosome biogenesis factor LSG1-2 is required for 40S maturation in A. thaliana.
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Carbohydrate conformation refers to the overall three-dimensional structure adopted by a carbohydrate (saccharide) molecule as a result of the through- bond and through-space physical forces it experiences arising from its molecular structure. The physical forces that dictate the three-dimensional shapes of all molecules—here, of all monosaccharide, oligosaccharide, and polysaccharide molecules—are sometimes summarily captured by such terms as "steric interactions" and "stereoelectronic effects" (see below). Saccharide and other chemical conformations can be reasonably shown using two-dimensional structure representations that follow set conventions; these capture for a trained viewer an understanding of the three-dimensional structure via structure drawings (see organic chemistry article, and "3D Representations" section in molecular geometry article); they are also represented by stereograms on the two dimensional page, and increasingly using 3D display technologies on computer monitors. Formally and quantitatively, conformation is captured by description of a molecule's angles—for example, sets of three sequential atoms (bond angles) and four sequential atoms (torsion angles, dihedral angles), where the locations and angular directions of nonbonding electrons ("lone pair electrons") must sometimes also be taken into account.
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As a rubber network is stretched, some kinks are forced into a restricted number of more extended conformations having a greater end-to-end distance and it is the resulting decrease in entropy that produces an elastic force along the chain. There are three distinct molecular mechanisms that produce these forces, two of which arise from changes in entropy that we shall refer to as low chain extension regime, IaD. E. Hanson and R. L. Martin, Journal of Chemical Physics 133, 084903 (084908 pp.) (2010) and moderate chain extension regime, Ib.D. E. Hanson, J. L. Barber and G. Subramanian, Journal of Chemical Physics 139 (2013), LAPR-2014-018991 The third mechanism occurs at high chain extension, as it is extended beyond its initial equilibrium contour length by the distortion of the chemical bonds along its backbone. In this case, the restoring force is spring-like and we shall refer to it as regime II.D. E. Hanson and R. L. Martin, The Journal of Chemical Physics 130, 064903 (2009), LAPR-2009-006764 The three force mechanisms are found to roughly correspond to the three regions observed in tensile stress vs. strain experiments, shown in Fig. 1.
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More recently, with the availability of a much wider variety of other molecular graphics tools, presentation use of kinemages has been overtaken by a wide variety of research uses, concomitant with new display features and with the development of software that produces kinemage- format output from other types of molecular calculations. All-atom contact analysis adds and optimizes explicit hydrogen atoms, and then uses patches of dot surface to display the hydrogen bond, van der Waals, and steric clash interactions between atoms. The results can be used visually (in kinemages) and quantitatively to analyze the detailed interactions between molecular surfaces, most extensively for the purpose of validating and improving the molecular models from experimental x-ray crystallography data. Both Mage and KiNG (see below) have been enhanced for kinemage display of data in higher than 3 dimensions (moving between views in various 3-D projections, coloring and selecting candidate clusters of datapoints, and switching to a parallel coordinates representation), used for instance for defining clusters of favorable RNA backbone conformations in the 7-dimensional space of backbone dihedral angles between one ribose and the next.
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Menerba has been reported to alleviate menopausal symptoms such as hot flashes, while having no stimulative effects on endometrium or breast tissue. In mouse xenograft models, Menerba produced a different conformation in estrogen receptor alpha (ERα) from ERβ when compared with the conformations produced by estradiol. The specific conformational change induced by Menerba allows ERβ to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. It has been shown that the increased risk of breast and uterine cancers is associated with ERα activation and that ERβ blocks the growth promoting effects on breast cancer cells. Menerba does not activate the ERα-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation, demonstrating that it may be a viable alternative for hormone therapy in comparison to estrogens that non- selectively activate both ER subtypes. In 2007, Menerba completed a multi- center Phase 2, double-blind, placebo-controlled randomized clinical trial evaluating its potential for the treatment of hot flashes in 217 healthy post- menopausal women in the U.S. The principal investigator of the trial was Dr. Deborah Grady from the University of California, San Francisco.
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The C-terminal extension, stabilized by the Cys16-Cys42 disulfide bond, consists of three y-turns, VI-VIII, that are, respectively, an inverse turn, centered on Thr33, a classic turn centered on Ile35 and an inverse turn centered on Phe39. All three of the y-turn hydrogen bonds have slowly exchanging amide protons (although this is not the case for the other turns). The only slowly exchanging amide proton not accounted for by consensus hydrogen bonds in any secondary structure element is that of Gly37 (which hydrogen bonds to Thr34 in one of the structures). The conformations of the Cys1-Cys15 and Cys8-Cys20 disulfide bonds are well defined and have negative and positive Xss, respectively; the other two bonds have lower order parameters. The hydrophobic core of RBX is limited, consisting of essentially the disulfide knot cystine residues and the buried Met18. However, the 22-28 loop contains one apolar residue, Ala23, and three aromatics, Tyr22, Trp24 and Tyr25, and is flanked by Ile21 at its N-terminus and Trp7 near its C-terminus, so this region represents a significant non-polar surface on the molecule. RBX is highly positively charged, with one Arg (sequence position 5) and six Lys (3, 4, 10, 19, 40 and 41) residues, balanced only by Glu12 and Asp13.
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