Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell
Open accessAbstract
All soluble proteins populate conformational ensembles that together constitute the native state. Their fluctuations in water are intrinsic thermodynamic phenomena, and the distributions of the states on the energy landscape are determined by statistical thermodynamics; however, they are optimized to perform their biological functions. In this review we briefly describe advances in free energy landscape studies of protein conformational ensembles. Experimental (nuclear magnetic resonance, small-angle X-ray scattering, single-molecule spectroscopy, and cryo-electron microscopy) and computational (replica-exchange molecular dynamics, metadynamics, and Markov state models) approaches have made great progress in recent years. These address the challenging characterization of the highly flexible and heterogeneous protein ensembles. We focus on structural aspects of protein conformational distributions, from collective motions of single- and multi-domain proteins, intrinsically disordered proteins, to multiprotein complexes. Importantly, we highlight recent studies that illustrate functional adjustment of protein conformational ensembles in the crowded cellular environment. We center on the role of the ensemble in recognition of small- and macro-molecules (protein and RNA/DNA) and emphasize emerging concepts of protein dynamics in enzyme catalysis. Overall, protein ensembles link fundamental physicochemical principles and protein behavior and the cellular network and its regulation.
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- Findingnone given
Cys322 is located in a well-formed helix critical for catalysis.
“Cys322 is located in a well-formed helix, which is critical for catalysis.”
Quote in the paperNot a substantial claim - Findingown data
REMD-predicted and experimentally measured Cα SCSs for K18 have a Pearson correlation coefficient of 0.614.
“The REMD-predicted and experimentally measured Cα SCSs show a Pearson correlation coefficient of 0.614 (Fig. 6 C), consistent with previous NMR data.371”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [371] source
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- Findingown data
K18 monomer has both ordered and disordered nature, as revealed by representative conformations of top eight most-populated RMSD-based clusters.
“Representative conformations of the top eight most-populated RMSD-based clusters (Fig. 6 A, B) reveal the both ordered and disordered nature of the K18 monomer.”
Quote in the paperNot a substantial claim - Findingown data
In K18 monomer, cysteine-containing sequences 283DLSNVQSKCGS293 in R2 and 314DLSKVTSKCGS324 in R3 transiently sample α-helical structure.
“Our REMD-generated data of K18 monomer show that cysteine-containing sequences 283DLSNVQSKCGS293 in R2 and 314DLSKVTSKCGS324 in R3 transiently sample α-helical structure (Fig. 7 A).”
Quote in the paperSubstantial claim - Premisecitation
In solution, protein conformational fluctuations cause even stable proteins to form ensembles of highly populated substates with thermodynamic population distributions.
“Conformational fluctuations of proteins in solution,11 as revealed mostly by nuclear magnetic resonance (NMR) experiments and computations, make even stable proteins exist as conformational ensembles with highly populated substates whose populations follow thermodynamic distributions.12–16”
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- Premisecitation
IDPs are expected to have higher heat capacity than well-defined proteins, potentially 2-4 times that of globular proteins of equal mass.
“Proteins with very flexible conformations, such as intrinsically disordered proteins (IDP), are expected to have larger heat capacity than well-defined proteins.96–98”
- Also stated in: § Intrinsic thermodynamic fluctuation of protein and water · hedged
“The heat capacity of IDP could be 2 to 4 times larger than globular proteins with the same molecular mass.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Also stated in: § Intrinsic thermodynamic fluctuation of protein and water · hedged
- Interpretationcitation
Population shifts within dynamic distributions provide the link to function and life.
“It is the dynamic change in the distributions – via population shifts – that portrays and captures the linkage to function and life.89”
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- Interpretationcitation
Energy fluctuations within a protein, together with water energy fluctuations of 10-20 kcal/mol, can drive a well-folded protein into many states.
“However, the intrinsic protein energy fluctuation coupled with the local energy fluctuations in water with a range of 10 to 20 kcal/mol,93–94 is enough to perturb a well folded protein to a vast number of states.”
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Protein structural fluctuations at equilibrium arise from both internal molecular interactions and energy fluctuations in the surrounding water.
“At thermodynamic equilibrium, structural fluctuations of proteins are not only induced by the fluctuations of intra-molecular interactions of proteins, but also by the fluctuations of the energy of the surrounding water molecules.”
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- Premisenone given
In solution, a protein is a dynamic equilibrium mixture of conformer sub-ensembles with different partial molar volumes.
“A protein molecule in solution exists in a dynamic equilibrium mixture of sub-ensembles of conformers differing in partial molar volumes.”
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Protein volume and solvent accessible surface area change together in a positive correlation.
“Changes in volume and SAS (solvent accessible surface area) are positively correlated.”
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Lower-volume conformations have their cavities occupied by solvent.
“In conformations with lower volume the cavities are filled with solvent.120–121”
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All soluble proteins exist as conformational ensembles in equilibrium around their native states.
“In the cell, the conformational ensembles of all soluble proteins are in equilibrium around their native states.1”
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- Premisecitation
Folding in small proteins, domains, and disordered states frequently follows a two-state mechanism with an energy barrier.
“In small proteins, domains, and disordered states, protein folding is often a two-state process132 separated by an energy barrier.”
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- Premisecitation
The breadth of conformational distributions varies among proteins, with some showing lower and some higher structural variability as measured by RMSD and other parameters.
“The breath of the distributions of the ensembles varies across proteins; some with lower and some with higher structural variability as measured by root-mean-square deviation (RMSD) and other parameters2.”
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- Premisenone given
Conformational fluctuations are directly linked to a protein's compressibility and heat capacity.
“The protein compressibility βT and heat capacity Cv or Cp are directly related to the conformational fluctuations of proteins.”
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A protein's biological function requires a conformational ensemble that is dictated by the energy landscape.
“more and more evidence indicates that the energy landscape dictates the conformational ensemble needed for the protein’s biological function.3”
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- Premisenone given
Natural proteins have smoother energy landscapes than random amino-acid sequences.
“Compared to random amino-acid sequences, the energy landscapes of natural proteins are smoother, in line with the funnel description.”
Quote in the paperNot a substantial claim - Interpretationnone given
A conformation with smaller volume tends to be more rigid.
“The lower the volume, the more rigid the conformation would be.”
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The calculated SAXS profile for the p53 tetramer agrees well with experiment.
“The calculated SAXS profile agrees well with the experiment.”
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- Interpretationnone given
Protein fluctuations tend to be larger when the global energy minimum is shallower.
“The shallower the global energy minimum, the larger the protein fluctuation is likely to be.”
Quote in the paperSubstantial claim - Premisecitation
Free K63-linked diubiquitin exists as a dynamic ensemble of multiple closed and open quaternary states, as shown by inter-subunit paramagnetic NMR.
“Analysis of inter-subunit paramagnetic NMR data showed that free K63-Ub2 exists as a dynamic ensemble comprising multiple closed and open quaternary states.”
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- Premisecitation
Multi-scale ensemble modeling of p53 with intrinsically disordered linkers illustrates how linkers encode states.
“This mechanism can be also illustrated by multi-scale ensemble modeling of p53 proteins with intrinsically disordered linker regions.227”
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- Premisecitation
In solvent, protein energy landscapes resemble those of glass and supercooled liquids.
“As compared to crystal, the energy landscapes of proteins in solvent are similar to those of glass and supercooled liquid.163”
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- Interpretationcitation
Recognition mechanisms are governed by the shape of the intrinsic energy landscape.
“The recognition mechanism depends on the topography of the intrinsic energy landscape.”
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- Premisecitation
Ligand binding sites close to catalytic sites may have moderate flexibility that accommodates ligand binding.
“Ligand binding sites which closely neighboring catalytic sites may enjoy moderate flexibility which accommodates ligand binding.221”
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Quaternary dynamics allows K63-Ub2 to be specifically recognized in various signaling pathways.
“Quaternary dynamics enables K63-Ub2 to be specifically recognized in a variety of signaling pathways.226”
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- Premisenone given
IDPs typically exhibit lower energy barriers.
“As indicated in Fig. 2, intrinsically disordered proteins generally have lower energy barriers.”
Quote in the paperNot a substantial claim - Interpretationcitation
Rather than one structure, the native state comprises many conformations that fluctuate at the funnel bottom with similar energies and low barriers.
“Therefore, on the energy landscape, the protein native state is not a single structure but a collection of conformations fluctuating at the bottom of the funnel with comparable energy and small energy barriers.160–161”
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Conformational entropy of the native state is set by the width and ruggedness of the global energy minimum.
“The width and ruggedness of the unique global energy minimum determine the conformational entropy of the native state.133”
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- Interpretationcitation
The distributions and variability of conformers provide a gradient of binding-site shapes and volumes.
“Depending on the distributions of the conformers and their conformational variability, they provide a gradient of binding site conformations of different shapes and volumes.”
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Hinge regions that adopt multiple conformations often act as binding sites for several ligands.
“Hinge sites with multiple conformations are often the binding sites for multiple-ligands,219”
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- Interpretationreasoning
A vast number of conformational states and thermodynamic fluctuations around the native state make the folding and interaction landscape necessarily rugged.
“Even with a funnel shape, the protein folding and interaction energy landscape is necessarily rugged since a vast number of conformational states and substates exist along the folding/binding pathway as well as thermodynamic fluctuations around native state.”
Quote in the paperSubstantial claim - Interpretationcitation
Multiple minima, connected by complex transition states, characterize the functional energy landscape.
“Consequently, the functional energy landscape has multiple minima, bridged by complex transition states.133”
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- Premisecitation
A target protein can select and stabilize one of the preexisting quaternary states of K63-Ub2.
“One of the preexisting quaternary states can be selected and stabilized by a target protein.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [226] source
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- Interpretationreasoning
Such binding-site conformational gradients can favorably interact with ensembles of ligands of different sizes.
“These can potentially favorably interact with ensembles of ligands of variable sizes.219,225”
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Fluorescence correlation analysis indicates that T4 lysozyme populates multiple intermediate states.
“Correlation analysis of fluorescence indicates that T4L populates multiple intermediate states.222”
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- Premisecitation
In allosteric proteins, hinges sit near high-frustration regions, allowing rare large-amplitude fluctuations that approach the opposite state basin.
“Their work confirmed that hinge regions are located near regions of high frustration, which enables allosteric proteins to exhibit rare and large-amplitude fluctuations nearly up to the opposite state basin.143”
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- Premisecitation
Simulations combined with experiments revealed details of the conformational ensemble of T4 lysozyme.
“A combination of simulations and experiments revealed details of the conformational ensemble of the T4L.223–224”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
Evolution has exploited landscape ruggedness to tune proteins for their functions.
“Nature has taken advantage of the ruggedness of the energy landscape to optimize proteins for their functions.”
Quote in the paperSubstantial claim - Premisecitation
Signal integration through inter-domain linkers often shows synergistic rather than simple additive responses to activating inputs.
“Biological signal integration through the inter-domain linkage often does not display simple additive responses to activating inputs; instead, the linker provides synergistic activation effects.217”
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- Premisecitation
Propagation of conformational change at certain locations can cause large-amplitude fluctuations of linked domains.
“The propagation of conformational change at certain locations228–230 can lead to large amplitude fluctuations of the linked domains.231”
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Amyloid aggregation is characterized by conformational transitions from intrinsic disorder in soluble monomeric/oligomeric forms to ordered self-assembled amyloid fibrils of the same proteins.
“Therefore, IDPs have also become the focus of studies of molecular mechanisms of amyloid aggregation, characterized by conformational transitions from intrinsic disorder in the soluble monomeric/oligomeric form to ordered self-assembled amyloid fibrils of the same proteins.262–263”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
The native conformational ensemble of inactive procaspase 3 is constrained by its intersubunit linker.
“The native conformational ensemble of inactive procaspase 3 is constrained by its intersubunit linker (IL).”
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- Interpretationcitation
In p53 and many other cases, the effect is direct recognition rather than an allosteric PTM acting through a population shift.
“Here, however, as in many other cases it is a direct recognition rather than an allosteric PTM functioning through a population shift.”
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- Premisecitation
The conformational ensemble of n16N, an intrinsically disordered peptide, has dominant structures that place key residues in locations thought critical for selective binding to β-chitin surfaces, as shown by REMD combined with NMR.
“However, a combination of replica exchange molecular dynamics simulations with NMR experiments showed that in the equilibrium conformational ensemble of the intrinsically disordered peptide the dominant structures present the key residues in locations thought to be critical for selective binding to β-chitin surfaces.258”
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- Premisecitation
Combinations of post-translational modifications can constitute an allosteric code.
“Combinations of PTMs can constitute an allosteric code.77”
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- Premisecitation
Cleavage of the intersubunit linker activates procaspase 3.
“Cleavage of the linker activates procaspase 3.”
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- Interpretationnone given
Disordered proteins provide evidence that protein function and properties are determined not only by static folded 3D structure but by the distribution and redistribution of the conformational ensemble.
“Disordered proteins provide evidence that the function of a protein and its properties are not only decided by its static folded three-dimensional structure; but by the distribution and redistribution of the conformational ensemble.”
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MD results reveal similar conformational ensembles for native and non-native ubiquitin dimers.
“The MD results also reveal similar conformational ensembles for the native and non-native ubiquitin dimers.”
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Disordered proteins account for a large fraction of all cellular proteins.
“Disordered proteins account for a large fraction of all cellular proteins.248”
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- Study design and conductcitation
Because SAXS data are low resolution and cannot precisely determine relative monomer orientation, MD-generated conformations differ somewhat from those fitted with the experimental structural library.
“It is noted that due to the low resolution nature of SAXS data which prevents a precise determination of relative orientation of the two monomers, the MD generated conformations differ somewhat from those fitted with the experimental structural library.232”
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- Premisecitation
SAXS profiles for ubiquitin dimers connected by native and non-native linkages are similar.
“They found that SAXS profiles for the two types of dimers are similar.”
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- Premisecitation
Increasing the intersubunit linker length by introducing 3-5 alanines can produce constitutively active procaspases.
“Interestingly, increasing the IL length by introducing 3–5 alanines can lead to constitutively active procaspases.236”
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- Premisecitation
A post-translational modification can bias the conformational distribution, increasing the population time of a cluster favored for binding a specific partner.
“A post-translational modification (PTM) can bias the conformational distribution, increasing the population time of a cluster favored for binding a specific partner77.”
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- Premisecitation
The L12 conformational ensemble shows that its two C-terminal domains sample a large volume and extend farther from the ribosomal anchor than expected for a random-chain linker, indicating residual order in the flexible linker.
“The ensemble of L12 conformations reveals that the two C-terminal domains sample a large volume and extend further away from the ribosomal anchor than expected for a random-chain linker, indicating that the flexible linker has residual order.”
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- Premisecitation
Intrinsically disordered proteins are on average twice as likely to be kinase substrates.
“Intrinsically disordered proteins are on average twice more likely to be substrates of kinases, highlighting the importance of post-translational modifications in fine-tuning function.254”
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- Premisecitation
The sequence of linkers and of residues contacting adjoining domains may encode successive or parallel states through which signals travel.
“The sequence of the linkers and of residues in contact between linkers and adjoining domains may encode successive or parallel states through which signals travel.29”
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- Interpretationreasoning
Stabilizing linkers may abolish function.
“Stabilizing such linkers may abolish function.”
Quote in the paperNot a substantial claim - Premisecitation
Releasing strain of the short intersubunit linker alone is insufficient to sufficiently increase the population of the active procaspase 3 conformer in the native ensemble.
“However, releasing the strain of the short IL is not enough to sufficiently increase the population of the active conformer in the native ensemble.”
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- Interpretationcitation
Analysis of tau protein conformational ensembles supports structured disorder and conformational selection as functional mechanism for IDPs.
“The results of the analysis of the conformational ensembles of the tau proteins support the view of structured disorder and conformational selection as functional mechanism for IDPs.377”
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- Interpretationown data
The REMD-generated conformational ensemble of K18 monomer is consistent with previous NMR data.
“These good correlations between the REMD- and NMR-derived Cα chemical shifts indicate that the REMD-generated conformational ensemble of K18 monomer is consistent with previous NMR data.371”
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- Premisecitation
The conformational selection and population shift model provides a more realistic description of molecular mechanism considering ensemble nature.
“The ‘conformational selection and population shift’ model87–89,134 provides a more realistic description of the molecular mechanism considering the ensemble nature of protein molecules.”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationcitation
Close lysine-cysteine contacts in K18 may facilitate tau's self-acetylation activity mediated by cysteine residues.
“The close lysine-cysteine contacts in K18 may facilitate tau’s self-acetylation activity mediated by cysteine residues as reported recently.379”
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- Premisecitation
Tau proteins have intrinsic enzymatic activity that catalyzes self-acetylation, mediated by a pair of catalytic cysteine residues in the MT-binding domain.
“Tau proteins possess intrinsic enzymatic activity capable of catalyzing self-acetylation mediated by a pair of catalytic cysteine residues residing within the microtubulin (MT)-binding domain.373”
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- Premisecitation
MSMs can predict kinetic quantities on long timescales (e.g., milliseconds) using shorter MD simulations.
“MSMs can predict kinetic quantities on long timescales (e.g. milliseconds) using a set of much shorter MD simulations.395–396”
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Symmetrical oligomeric complexes are evolutionarily selected by functional, genetic, and physicochemical needs.
“Symmetrical oligomeric complexes are evolutionarily selected by functional, genetic, and physicochemical needs.”
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- Premisereasoning
MSMs can identify kinetically relevant states and rates of interconversion between them.
“A Markov state model (MSM), known as a stochastic model, provides an approach which can be used to identify the kinetically relevant states and the rates of interconversion between these states.”
Quote in the paperNot a substantial claim - Premisecitation
Metadynamics methods have been successfully applied to study free energy landscapes of flexible proteins, protein oligomers, peptide folding, ligand and selective ion permeation through membrane channels.
“These methods alone, or in combination with high-resolution experimental techniques such as x-ray crystallography and NMR, have been successfully applied to the study of the free energy landscape of flexible proteins and protein oligomers,36,388–389 peptide folding,390–392 ligand and selective ion permeation through cell membrane protein channels.393”
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The two cysteine-containing regions of K18 are highly similar to catalytic regions in MYST-family acetyltransferases Esa1 and Tip60.
“These two regions are highly similar to the catalytic regions in MYST-family acetyltransferase Esa1 and Tip60.379”
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- Premisecitation
Protein-protein interfaces are characterized by hot spots or hot regions rather than even contribution across all contact areas.
“Protein-protein interfaces are characterized by the existence of hot spots or ‘hot regions’ in interacting regions instead of an even contribution across all contact areas.371,476,487,492–495”
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- Interpretationcitation
The structural ensemble in DHFR is exquisitely optimized for every intermediate in the catalytic cycle.
“The structural ensemble in DHFR is exquisitely optimized for every intermediate in the catalytic cycle.461”
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- Interpretationnone given
Conformational ensemble heterogeneity promotes enzyme promiscuity.
“It is easy to understand that conformational ensemble heterogeneity promotes enzyme promiscuity.”
Quote in the paperSubstantial claim - Interpretationreasoning
Conformational ensembles enable enzymes to function through multiple steps.
“Conformational ensembles enable enzymes to function through multiple steps.”
Quote in the paperSubstantial claim - Premisecitation
Using experimentally known protein conformational ensembles in proteome-scale modeling of protein-protein interactions boosts successful prediction from ~26% to 66%.
“Using experimentally known protein conformational ensembles in modeling protein-protein interactions on the proteome scale can boost the percentage of successfully predicted interactions from ~26 to 66%.478”
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- Premisecitation
In >70% of 98 examined enzymes, GNM-predicted global hinge centers colocalize with experimentally identified catalytic sites.
“They found that in more than 70% of the examined enzymes, the global hinge centers predicted by the GNM are colocalized with the experimentally identified catalytic sites.”
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- Premisecitation
The rate of enzyme conversion of substrates to products is not the speed of the chemical step.
“The rate by which the enzyme converts substrates into products is not the speed of the chemical step.448”
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- Premisenone given
Protein-protein interactions and other cellular networks can adjust internal states to incoming stimuli.
“Protein-protein interactions and other cellular networks have the ability to adjust their internal states to incoming stimuli.”
Quote in the paperSubstantial claim - Premisecitation
MD simulations and free energy calculations revealed a crucial role of protein flexibility in forming a stable reaction transition state in α-amylase catalysis.
“MD simulations and free energy calculations revealed the crucial role of protein flexibility in formation of a stable reaction transition state in α-amylase catalysis.451”
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- Premisecitation
Enzymes are optimized by evolution to exploit conformational ensembles to recognize substrates and stabilize transition states.
“Enzymes are optimized by evolution to exploit conformational ensembles to recognize their substrates and stabilize the transition states,70,209 and both experimental and theoretical evidence indicates that enzyme conformational transitions are highly organized which increases enzyme specificity and efficiency.133,399,433–435”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Ensemble receptor-based protocols have stronger discriminating power between active and inactive molecules than standard single rigid receptor protocols.
“Overall, ensemble receptor-based protocols display a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart.426”
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- Premisecitation
SOS functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes rather than the ensemble average.
“It has been shown that SOS functional output may be determined by the dynamical spectrum of rates sampled by a small number of enzymes, rather than the ensemble average.472”
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- Premisecitation
During binding, higher energy (lower population) conformers most complementary to pre-existing ligand conformations can be selected, shifting equilibrium toward them.
“During binding, higher energy (lower population) conformers which are most complementary to some pre-existing ligand conformations can be selected and the equilibrium shifts toward these conformers.87–89,134”
Quote in the paperSubstantial claim0 of 4 sources checked - Interpretationcitation
MUP-I's ability to bind different lipophilic ligands derives from limited conformational flexibility and unoccupied space in the hydrophobic β-barrel interior.
“In this case, the ability of MUP-I to bind different lipophilic ligands derives from a limited extent of conformational flexibility and unoccupied space within the hydrophobic interior of the β-barrel.413”
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- Premisenone given
Interactions of IDPs with small molecules are harder to track experimentally or computationally than globular proteins with flexible binding sites.
“As compared to globular proteins with flexible binding sites, the interactions of intrinsically disordered proteins with small molecules are much harder to track either experimentally or computationally.”
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Targeting α-synuclein's disordered structural ensemble by small molecules is promising as a therapeutic strategy for Parkinson's disease.
“Targeting the intrinsically disordered structural ensemble of α-synuclein by small molecules as a potential therapeutic strategy for Parkinson’s disease has been shown to be promising.429”
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Protein dynamics are universally important for protein-ligand interaction.
“Protein dynamics have been shown to be universally important for protein-ligand interaction.219”
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- Premisecitation
For bacterial phosphotriesterase, maltose binding protein, choline oxidase, cytochrome bc1 complex, and many lid-gated enzymes, closed and open conformations are in equilibrium prior to ligand binding, permitting conformational selection at different catalytic steps.
“Conformational sampling for bacterial phosphotriesterase,443 maltose binding protein,444 and choline oxidase,445 cytochrome bc1 complex,446 and many other lid-gated enzymes indicated that the closed and open conformations are in equilibrium prior to ligand binding, permitting a conformational selection pathway at different catalytic steps.447”
Quote in the paperSubstantial claim0 of 5 sources checked - Interpretationcitation
Enzyme specificity can be controlled through multiple conformational selection steps.
“Enzyme specificity can be controlled through multiple conformational selection steps.”
Quote in the paperSubstantial claim - Interpretationcitation
Ensemble-averaged states are sometimes not applicable to enzymes with distinct functional states.
“Ensemble-averaged states sometime are not applicable to enzymes with distinct functional states.”
Quote in the paperSubstantial claim - Premisenone given
Different protein conformations often correspond to different biological functions.
“Different protein conformations often correspond to different biological functions.”
Quote in the paperSubstantial claim - Premisenone given
Catalytic power of enzymes largely derives from stabilizing transition states, lowering the barrier.
“The catalytic power of enzymes largely derives from their ability to stabilize transition states, lowering the barrier that reactants have to pass to reach productive states.”
Quote in the paperNot a substantial claim - Premisecitation
ATP turnover by individual myosin molecules uses two conformers of the active site: one allowing complete ATPase cycle, one dissociating ATP uncleaved.
“Recently, it has been found that ATP turnover by individual myosin molecules uses two conformers of the myosin active site, one that allows the complete ATPase cycle and one that dissociates ATP uncleaved.467”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [467] source
Not checked in the free run.
- Premisecitation
Serine protease, conventionally regarded as rigid lock-and-key, shows nanosecond timescale binding loop movement that selects an inhibitor conformation.
“Serine protease is conventionally regarded as fitting the rigid lock-and-key model. However, nanosecond timescale binding loop movement was observed to select an inhibitor conformation.465”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [465] source
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- Premisecitation
Residues surrounding conserved residues can form a flexible cushion.
“whereas the residues surrounding the conserved residues may form a flexible cushion.496”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [496] source
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- Premisecitation
Antibody evolution may constrain conformational heterogeneity by tailoring protein dynamics.
“Antibody evolution may constrain conformational heterogeneity by tailoring protein dynamics.519”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [519] source
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- Interpretationreasoning
Combining rigid hot spot regions with flexible protein regions can efficiently tune the energy of protein-protein interactions.
“Coupling of rigid hot spot and flexible protein regions can be an efficient way to adjust protein-protein interaction energy.”
Quote in the paperSubstantial claim - Premisecitation
Mutations in antifluorescein antibody 4-4-20 localized its combining site from a heterogeneous ensemble to a single conformation by cooperative long-range rigidification.
“Controlled evolution of the antifluorescein antibody 4–4-20 localized the Ab-combining site from a heterogeneous ensemble of conformations to a single conformation by introducing mutations that act cooperatively and over significant distances to rigidify the protein.519”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [519] source
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- Premisecitation
Point mutations in the ubiquitin core change binding specificity allosterically by shifting the ground-state ensemble between open and closed substates that have similar populations in the wild-type protein.
“Antibody evolution and conformational changes are similar to point mutations within the ubiquitin core, which changes the binding specificity allosterically by shifting the conformational equilibrium of the ground-state ensemble between open and closed substates that have similar populations in the wild-type protein.521”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [521] source
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- Premisecitation
Correlated flexibility may increase during antibody complex formation.
“It was also found that correlated flexibility may increase during antibody complex formation.520”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [520] source
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- Premisecitation
Eph-ephrin specificity is controlled not only at the final protein-protein interface but also by dynamic intermediate stages along the recognition pathway.
“The results indicated that the specificity is not only controlled by the final stage of the interaction across the protein-protein interface, but also contributed by dynamic intermediate stages along the pathway from the separated Eph and ephrin to the Eph-ephrin complex.514”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [514] source
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- Premisecitation
Two scFv mutants with similar thermodynamic stability show local and long-range changes in backbone flexibility.
“In comparing two scFv mutants with similar thermodynamic stability, local and long-ranged changes in backbone flexibility are observed.520”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [520] source
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- Interpretationcitation
Antibody-antigen interactions optimize the coupling of rigid and flexible binding sites for specific antigen binding.
“Antibody-antigen interactions optimize the coupling of rigid and flexible protein binding sites for specific antigen binding.”
Quote in the paperNot a substantial claim- Rests on an assumption: Antibody variable regions must be flexible to recognize highly diversified targets.
- Premisecitation
SAXS analysis of identical variable regions from IgG1, IgG2, and IgG4 reveals distinct subclass-specific conformational preferences.
“The ensembles were optimized through shape clustering, revealing distinct subclass-specific conformational preferences.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [517] source
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- Premisecitation
This flexibility mechanism appears additional to other hub-protein mechanisms such as covalent linkage to interaction domains and alternative splicing.
“This mechanism appears to be in addition to other mechanisms adopted by hub proteins, such as covalent linkage to protein interaction domains, alternative splicing variants, etc.524”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [524] source
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- Interpretationreasoning
In multiple-partner binding or altered homo-multimeric organization, different binding modes use distinct conformers from the ensemble, explaining promiscuous binding.
“In cases of multiple-partner binding, or in altered homo-multimeric organization, the different binding modes are accomplished through distinct conformers from the ensemble, explaining the so-called ‘promiscuous’ binding.”
Quote in the paperSubstantial claim - Premisecitation
Human centrosomal proteins are significantly biased toward being unstructured and having coiled-coil regions compared with generic human proteins.
“Bioinformatics analysis indicated that human centrosomal proteins have a significant bias to be both unstructured and with coiled-coil regions with respect to generic human proteins.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [526] source
Not checked in the free run.
- Premisecitation
Differences in the linker region correlate with the solution structure of intact antibodies.
“The specific differences in the linker region correlate with the solution structure of intact antibodies.517”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [517] source
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- Premisecitation
Conformational dynamics and the distribution of the conformational ensemble are important in Eph-ephrin recognition.
“Conformational dynamics and the distribution of the conformational ensemble are important in Eph-Ephrin recognition.9,475,513–516”
Quote in the paperSubstantial claim0 of 6 sources checked - Premisereasoning
Protein-protein interactions can span a broad range of binding energies.
“Depending on the function of the complex, protein-protein interactions may have a broad range of binding energies.”
Quote in the paperNot a substantial claim - Interpretationcitation
A wide conformational ensemble enables hub proteins to bind many partners with different binding modes.
“The wide distribution of the conformational ensemble of flexible protein enables hub proteins to bind a large number of partners with different binding modes.”
Quote in the paperSubstantial claim - Premisecitation
Several hot spots in the Eph binding pocket are important for binding several peptides.
“Several hot spots in the Eph binding pocket were identified as important for the binding of several peptides.475”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [475] source
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- Premisecitation
Evidence of conformational selection driving formation of ligand binding sites in protein-protein interfaces was shown in a study using NMR ensembles of ligand-free protein conformations.
“Evidence of conformational selection driving the formation of ligand binding sites in protein-protein interfaces has been shown in one study which focused on ensembles of ligand-free protein conformations obtained by NMR.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [502] source
Not checked in the free run.
- Interpretationreasoning
A large interface area does not necessarily imply high binding affinity.
“but the large interfaces area does not necessarily equate to high affinities.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Changes and optimization of the conformational ensemble also allow allosteric antibody interaction.
“The change and optimization of the conformational ensemble also allow allosteric antibody interaction.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Highly fluctuating conformations of intrinsically disordered proteins provide functional advantages in protein-protein interactions.
“Highly fluctuating conformations of intrinsically disordered proteins offer functional advantages in protein-protein interactions.”
Quote in the paperSubstantial claim- Rests on an assumption: Natively disordered proteins can form ordered complexes upon binding their partner.
- Interpretationcitation
Eph-ephrin recognition illustrates how rigid and flexible binding sites can adjust promiscuous and specific protein-protein interactions.
“Eph-Ephrin recognition is a good example for the coupling of rigid and flexible protein binding sites to adjust ‘promiscuous’ and specific protein-protein interactions.”
Quote in the paperNot a substantial claim - Premisecitation
Hot spot residues at binding interfaces are rigid, which reduces the entropic cost of binding.
“Hot spot residues at binding interfaces confer rigidity to minimize the entropic cost of binding”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [496] source
Not checked in the free run.
- Interpretationreasoning
Nature used conformational selection to fit specific targets.
“Clearly, nature utilized conformational selection to fit specific targets.”
Quote in the paperSubstantial claim - Premisecitation
An ensemble model of yeast pheromone signaling generated reliable responses matching experimental observations.
“They found that the ensemble model generated reliable responses that match experimental observations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [535] source
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- Premisecitation
KIX is an allosteric domain that can bind two other proteins cooperatively.
“KIX is an allosteric domain able to bind two other proteins cooperatively.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [530] source
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- Premisecitation
Different partners binding at the second site can modulate pKID-KIX interaction conformations and affinity, regulating the transactivation complex.
“Different partners binding at the second site can modulate the conformations and thus the affinity of pKID-KIX interaction, regulating the transactivation complex.530”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [530] source
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- Premisecitation
In muscle contraction, release of chemical energy is often accompanied by thermal fluctuation, which can transform muscular force via cyclical myosin-actin interactions.
“In the classic example of muscle contraction as biomolecular machines, the release of chemical energy is often accompanied by thermal fluctuation, which can transform muscular force generated in response to external stimuli through cyclical interactions between myosin and actin.539”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [539] source
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- Premisecitation
Gene regulation complexity requires a combination of high- and low-affinity DNA binding.
“The complexity of gene regulation requires a combination of high and low affinity DNA binding.543”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [543] source
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- Premisecitation
Ensembles can signal effectively at the cellular systems level through a multiple-conformations combinatorial scheme representing weak linkage.
“The results illustrated on the cellular systems level that ensembles are able to signal effectively through a multiple-conformations combinatorial scheme that represents a form of weak linkage.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [535] source
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- Premisecitation
A hierarchical assembly model for scaffold-based signaling machines could not replicate experimental observations.
“In contrast, the model that employs hierarchical assembly pathways to produce scaffold-based signaling machines could not replicate experimental observations.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [535] source
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- Premisecitation
RNA and DNA exist as conformational ensembles in freely diffusing states, crystals, nucleosomes, ribosomes, and spliceosomes.
“RNA and DNA also exist as conformational ensembles, no matter whether in freely diffusing state,540 in crystal,541 or in large nucleosomes,542 ribosomes, or spliceosomes.”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
Ensembles conceptualize parallel signaling pathways whose abundance reflects cofactor and second messenger concentrations and cell states, including post-translational modifications.
“Ensembles conceptualize parallel signaling pathways whose abundance reflect concentrations of cofactors and second messengers and cell states, including interplay with post-translational”
Quote in the paperSubstantial claim - Interpretationnone given
Conformational ensembles are essential for molecular machine tasks requiring high specificity.
“Conformational ensembles are essential for molecular machine tasks requiring high specificity.”
Quote in the paperSubstantial claim - Interpretationcitation
A conventional mechanical description of protein complexes requiring well-defined quaternary structures is misleading because signaling and regulatory complexes are highly dynamic ensembles.
“Since signaling and other regulatory complexes typically consist of highly dynamic molecular ensembles a ‘conventional’ mechanical description of protein complexes that requires well-defined quaternary structures is misleading.534–535”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Enzymes and molecular motors can be described thermodynamically by ensembles of discrete states.
“Thermodynamically, both enzymes and molecular motors can be described by ensembles of a discrete set of states.532–533”
Quote in the paperSubstantial claim0 of 2 sources checked
- May combine two claims. 61
- Classified as probably not a substantial claim. 8
May combine two claims.
FindingreasoningA volume change of −20 to −100 mL/mol translates to a free energy change of −0.5 to −2 kcal/mol per kbar, enough to alter which conformational state dominates at high pressure.
“In a typical case, the partial molar volume change is about −20 to −100 mL/mol, which means the free energy change is on the order of −0.5 to −2 kcal/mol per 1 kbar which may be sufficient to shift state B as the dominant species under elevated pressure in place of state A.”
Quote in the paperSubstantial claimMay combine two claims.
FindingreasoningFor a typical 25 kDa protein, the root mean square fluctuations of energy and volume are approximately 38 kcal/mol and 80 Å3, respectively.
“One could estimate that the root mean square fluctuations of E and V are respectively:16 〈ΔE2〉≈38kcalmol−1, 〈ΔV2〉≈80Å3.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] source
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Findingown dataThe lysine-cysteine distance distribution in K18 shows peaks between 5 and 10 Å, indicating the two residues are close enough as in acetyltransferase (Cα−Cα distance 8.4 Å between Lys262 and Cys304).
“The lysine−cysteine distance distribution curve in Fig. 7 (B) displays peaks between 5 and 10 Å, indicating that the two residues are close enough as in acetyltransferase with a Cα−Cα distance of 8.4 Å between Lys262 and Cys304.380”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [380] source
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PremisecitationWhen projected onto a coordinate like the fraction of native contacts, the folding landscape appears as a funnel, which resolves Levinthal's paradox.
“Mapping the folding landscape to a single coordinate, such as the fraction of native contacts, the energy landscape can be visualized as a funnel,132 elegantly resolving Levinthal’s paradox.11”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationGreater protein flexibility correlates with more populated states, and disordered states lie at the extreme of this range.
“The more flexible are the proteins the larger the number of their populated states, with the disordered state being at the end of this spectrum.17”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] source
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PremisecitationStatistical energy landscape theory originated as a framework for studying protein folding.
“The statistical energy landscape theory was developed to study protein folding.1,128–131”
Quote in the paperNot a substantial claim0 of 5 sources checkedMay combine two claims.
PremisecitationWithin one unit cell, crystal proteins may adopt different conformations, and the crystal state does not capture multiple populated substates.
“It is now generally accepted that crystal proteins may still have different conformations in a single unit cell,9 and there are multiple, populated substates that are not captured in the crystal state.10”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisereasoningUnder pressure, a protein can reduce its volume either by elastic compression within a sub-ensemble or by shifting its conformational equilibrium toward low-volume conformers.
“There are two mechanisms for a protein in solution to attain a lower volume in response to pressure: ‘elastic response’ by general compression within the sub-ensemble of the conformers and a shift of the conformational equilibrium from a high-volume to a low-volume ensemble.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationProtein structures have intrinsic thermodynamic fluctuations, as do water molecules.
“Protein structures must be considered as dynamic objects at the molecular level due to their intrinsic thermodynamic fluctuations16,92 as well as those of water.93–94”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
Interpretationnone givenStatistical thermodynamics determines the distribution of states on the energy landscape, but function, optimized by evolution, also modulates these distributions.
“Here our thesis is that the distributions of the states on the energy landscape are determined by statistical thermodynamics; however, they are also modulated by function which is optimized by evolution.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Protein function has been optimized by evolution.
May combine two claims.
PremisecitationThermodynamic fluctuations sample pre-existing conformations; function arises from changing their relative populations, not from creating new conformations.
“The pivotal concept that all conformations pre-exist and are sampled by thermodynamic fluctuations – with function involving not new conformations but a shift in their relative concentration – underlies current approaches and interpretations.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationcitationAccording to the minimum frustration principle, evolution has optimized folding, and mutations perturb the landscape much like temperature changes.
“The minimum frustration principle implies that nature has optimized protein folding,129,174 thus the effect of point mutations on the energy landscape is analogous to thermal perturbations.175”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationRough energy landscapes slow dissociation and may strengthen the dynamic interaction between streptavidin and biotin.
“For example, the energy landscape roughness slows down dissociation kinetics and can contribute to streptavidin-biotin interaction dynamic strength.176”
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PremisecitationThe energy landscape framework now covers protein-ligand binding and function, with statistical methods modeling the binding landscape.
“The energy landscape concept was extended to protein-ligand binding and function87–89,134–141 and statistical approaches were developed to describe the protein binding energy landscape.142–158”
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- cites [134] source
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PremisecitationProtein motions fall into slower α and faster βh fluctuations; solvent viscosity governs α motions, while the hydration shell largely drives βh fluctuations.
“Exploiting the concept of glasses and supercooled liquids,166 protein motions could be classified by the α fluctuation (primary) and βh fluctuation (secondary).167–168 The slower α relaxation motions are inversely controlled by the solvent viscosity169–170 and the faster βh fluctuations are largely due to the hydration shell of the proteins.171”
Quote in the paperNot a substantial claim0 of 5 sources checkedMay combine two claims.
PremisecitationLong-range contacts in the p53 linker region were required to reproduce the experimental SAXS profile, indicating allosteric communication.
“However, long-range contacts in the p53 linker region were required to reproduce the experimental SAXS profile, indicating allosteric communication.227”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [227] source
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PremisecitationMutations at hinge regions can allosterically change binding-site dynamics or create alternative binding modes by altering the set of accessible conformations.
“mutations at the hinge regions could allosterically affect the binding-site dynamics or induce alternative binding modes by modifying the ensemble of accessible conformations220.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [220] source
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PremisereasoningFluctuation energy scales with the local glass transition temperature, while the folding frustration ratio TF/TG scales inversely with it.
“The local glass transition temperature TG is proportional to the fluctuation energy, and therefore the protein folding frustration TF/TG is inversely proportional to the fluctuation energy.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThe linker sequence is not randomly distributed, and the resulting calmodulin linker conformational ensemble must be optimized for calmodulin binding.
“The results indicated that the linker sequence is not randomly distributed; the resulting conformational ensemble of the linker must be optimized for calmodulin binding.234”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [234] source
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PremisecitationIn p53, phosphorylation at Ser20 turns off p53-MDM2 binding and increases p53 concentration, while phosphorylation at Thr155 targets p53 for ubiquitin-mediated degradation.
“In the case of p53, phosphorylation at Ser20 turns off p53-MDM2 binding, with a consequent increase in p53 concentration; while phosphorylation at Thr155 targets p53 to degradation by the ubiquitin system (reviewed in256).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [256] source
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PremisecitationDisordered proteins lack a stable, well-defined structure under physiological conditions and exist in a continuum from less to more structured states.
“‘Disordered’ or ‘intrinsically unstructured’ proteins lack a stable, well-defined structure under physiological conditions, existing in a continuum of conformations from the less to the more structured states.240–243”
Quote in the paperSubstantial claim0 of 4 sources checkedMay combine two claims.
PremisecitationMany proteins either contain at least one intrinsically disordered region or are completely disordered.
“Many proteins either contain at least one intrinsically disordered region (IDR) (such as intrinsically disordered domains and linkers in multidomain proteins)234,237 or are completely disordered (such as IDPs which are highly flexible and dynamic).238–239”
Quote in the paperNot a substantial claim0 of 4 sources checkedMay combine two claims.
Interpretationnone givenThe active state for a specific function is unique, unlike inactive states, and its stability or population can increase through an ensemble shift, such as by binding.
“The active state of a specific function is a unique state, which is not the case for the inactive states; its stability (population) may increase through a shift of the ensemble, e.g. via binding.”
Quote in the paperSubstantial claim- Rests on an assumption: For a given protein function, the active state is unique while inactive states are not unique.
May combine two claims.
PremisecitationThe PaaA2 antitoxin is highly compact in solution and exists as two preformed helices connected by a flexible linker, where the helices may act as molecular recognition elements for toxin inhibition.
“The conformational ensemble of PaaA2 is highly compact and in solution the protein exists as two preformed helices, connected by a flexible linker where the helices may act as molecular recognition elements for toxin inhibition.259”
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PremisecitationKukic et al. identified 10 residues in the calmodulin interdomain linker that change conformation upon substrate binding, including five flexible and five rigid residues.
“They identified 10 residues in the interdomain linker region that change their conformations upon substrate binding, including five flexible residues (Met76, Lys77, Thr79, Asp80 and Ser81) and five rigid residues (Arg74, Lys75, Asp78, Glu82 and Glu83).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [234] source
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Premisecitationp53 has more than a dozen phosphorylation and acetylation sites with different biological signals.
“One such example is the p53 protein, which has more than a dozen phosphorylation and acetylation sites with different biological signals.256”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [256] source
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PremisecitationThe structures of disordered proteins are not random; the disordered state has significant metastable structures.
“The structures of disordered proteins are not ‘random’. Rather, the disordered state has significant metastable structures.240–243,257”
Quote in the paperSubstantial claim0 of 5 sources checkedMay combine two claims.
InterpretationreasoningThe apparent challenge to the paradigm that function requires distinct 3D structure is not real, because function involves a specific selected state that may have marginal stability and low barriers, giving short residence times that can evade detection.
“Even though they appear to challenge the paradigm of structural biology, that function requires distinct 3D structure, this is not the case, since function involves a specific selected state, which may have marginal stability and low barriers, thus short residence time which may evade detection.”
Quote in the paperNot a substantial claim- Rests on an assumption: For a given protein function, the active state is unique while inactive states are not unique.
May combine two claims.
PremisecitationRegulation of unstructured proteins in cells can occur at multiple levels of mRNA transcription and degradation, protein translation and degradation, and fidelity control including post-translational modifications.
“The regulation of unstructured proteins in the cell can occur at multiple levels of mRNA transcription and degradation; protein translation and degradation; and fidelity control of transcription and translation, including post-translational modifications in functional/degradation control.254”
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PremisecitationOptimal linker length, intersubunit linker flexibility, and specific contacts between the linker and interface are needed to stabilize the active procaspase 3 state.
“The combination of optimal length, IL flexibility, and specific contacts between the IL and interface are needed to stabilize the active state.”
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PremisecitationAnti-correlation of distances between each L12 C-terminal domain and the anchor promotes L12's function in recruiting translation factors and controlling their ribosomal activity.
“It was suggested that anti-correlation of the distances between each C-terminal domain and the anchor promotes the function of L12 to recruit translation factors and control their activity on the ribosome.235”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [235] source
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PremisecitationIntrinsically disordered linkers connecting folded domains and intrinsically disordered domains usually encode conformational flexibility essential for protein function, including regulation of transcription and translation, cellular signaling, phosphorylation, regulation of large self-assemblies, and small molecule storage.
“Intrinsically disordered linkers connecting folded domains and intrinsically disordered domains usually encode the degrees of conformational flexibility essential for protein function,17,29,244–250,239,247,249–253 including regulation of transcription and translation, cellular signaling, phosphorylation, regulation of large multi-molecular self-assemblies and small molecule storage.249”
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- cites [244] source
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- cites [249] source
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PremisecitationInduced fit hypothesis suggests bound conformation can be induced by binding partner when complex conformation differs from unbound.
“The ‘induced fit’ hypothesis412 suggests that the bound conformation can be ‘induced’ by the binding partner when the conformation in the complexes differs from that in the unbound form.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [412] source
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PremisecitationHistone tail conformational ensembles consist of states with varying residual order; most tails are not fully disordered and exhibit distinct organization including α-helical elements and β-hairpins.
“demonstrated that the conformational ensembles of histone tails are composed of states with various degrees of residual order and most tails are not fully disordered, but show distinct conformational organization, containing α-helical elements and β-hairpins.368”
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InterpretationreasoningMSMs have potential to identify putative allosteric binding sites or differentiate agonists/antagonists using conformational information along functional pathways.
“Overall, these studies revealed the potential of MSMs to identify putative allosteric binding sites or to differentiate between agonists and antagonists using conformational information along putative functional pathways.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOligomeric proteins with two or more subunits make up about one third of cellular proteins, and most are symmetrical.
“Oligomeric proteins with two or more subunits comprise about one third of the cellular proteins,266–267 most of them symmetrical.266”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationIDPs adopt multiple conformations for function; multiple conformational ensembles collectively determine functions.
“IDPs adopt multiple conformations for function;377–378 that is, the multiple conformational ensembles collectively determine functions.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationMSMs have been applied to protein folding, ligand binding, conformational change, IDP dynamics/kinetics, and ATP permeation.
“Markov state models have been applied to a wide variety of problems, spanning protein folding,402 protein-ligand binding process,403 protein conformational change,404–405 the dynamics and kinetics of IDPs,369,406–407 and ATP permeation through membrane protein channels.408”
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PremisecitationProteins and their binding partners are flexible and exist in ensembles with certain conformational distributions.
“Proteins and their binding partners are flexible and exist in ensembles with certain conformational distributions.”
Quote in the paperSubstantial claim0 of 4 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMetadynamics is an enhanced sampling method widely used to explore conformational space of biomolecules.
“Similar to the REMD method, metadynamics is also an enhanced sampling method which is widely used to explore the conformational space of biomolecules.314,381”
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Premisenone givenREMD and metadynamics can provide structural and thermodynamic properties of proteins but do not reproduce kinetic rates and conformational dynamics.
“Enhanced sampling methods such as REMD and metadynamics can provide the structural and thermodynamic properties of proteins. However, they do not reproduce kinetic rates and conformational dynamics.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAcetylation of tau inhibits its function and promotes pathological aggregation.
“Acetylation of tau inhibits its function and promotes pathological aggregation.373–375”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMD simulations of CypA show enzyme conformational ensembles recognize diverse inhibitors and bind different configurations of peptide substrate.
“Molecular dynamics simulations of CypA show that the ensembles of enzyme conformations recognize diverse inhibitors and bind different configurations of the peptide substrate.3”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] source
Not checked in the free run.
May combine two claims.
PremisecitationGPCRs exhibit multiple inactive and active conformations, and ligand binding alters the population balance between them.
“GPCRs exhibit multiple inactive and active conformations, and the population balance between these conformations is altered upon binding of ligands.415”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [415] source
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InterpretationcitationProtein conformational ensemble allows enzymes to catalyze multiple chemical steps and accommodates conformational reorganization required to stabilize transition states.
“The protein conformational ensemble not only allows enzymes to catalyze multiple chemical steps, but accommodates the conformational reorganization required to stabilize the transition states.449”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [449] source
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PremisecitationThe docking algorithm achieved 93% success on 10 protein ensembles (105 crystal structures, 87 ligands), significantly better than single rigid-receptor docking (75% average).
“The docking algorithm was validated on 10 protein ensembles containing 105 crystal structures and 87 ligands and achieved a success rate of 93%, significantly better than single rigid-receptor docking (75% on average).425”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [425] source
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InterpretationcitationReceptor activation depends on both low energy states and the range of conformations sampled by the receptor.
“Therefore, receptor activation depends on both low energy states and the range of the conformations sampled by the receptor.416”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [416] source
Not checked in the free run.
May combine two claims.
PremisecitationR55K substitution at CypA active site significantly decreases catalysis, indicating active site stability likely plays an important role in the chemical step.
“An earlier QM/MM study468 demonstrated that R55K substitution at the active site of CypA leads to a significant decrease in catalysis, indicating that the active site stability likely plays an important role in the chemical step of catalysis.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [468] source
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PremisecitationLigands can interact with similar targets in different conformations, and biological outcomes such as ERβ selective agonist depend on relative affinities of a ligand to ensembles of protein conformations.
“It has been shown that ligands can interact with similar targets in different conformations, and that the biological outcomes like ERβ selective agonist depend on the relative affinities of a ligand to ensembles of protein conformations.414”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [414] source
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Premisecitationc-Myc binding conformations are partially formed in the apo ensemble, suggesting conformational selection.
“Comparison of the apo and holo equilibrium ensembles reveals that c-Myc binding conformations are already partially formed in the apo ensemble, suggesting a conformational selection mechanism.432”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [432] source
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InterpretationcitationProtein motions necessary for catalysis may be an intrinsic property of the enzyme and might limit overall turnover rate.
“This correlation could suggest that protein motions necessary for catalysis are an intrinsic property of the enzyme and might even limit the overall turnover rate.469”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [469] source
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InterpretationcitationIn AlkB, conformational ensemble and population shift allow co-substrate binding prior to substrate and limit premature substrate release.
“The conformational ensemble and population shift allow the enzyme to bind the co-substrate prior to the substrate, and can also limit premature release of substrate.442”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [442] source
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PremisecitationThe disordered state has significant metastable structure character, and functionally relevant conformations may have higher population times than other conformations.
“The disordered state has a significant metastable structure character240–243,257 and functionally relevant conformations may have population times higher than of other conformations.240–242”
Quote in the paperSubstantial claim0 of 5 sources checkedMay combine two claims.
PremisecitationPromiscuous residues tend to be more flexible, and this flexibility permits a broader range of organizations in different conformers.
“They found that promiscuous residues tend to be more flexible, and this additional flexibility permits a broader range of organizations which could take place in different conformers in the ensemble.523”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [523] source
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PremisecitationThe most flexible proteins are disordered proteins, with some more folded than others.
“Obviously, the most flexible proteins are the disordered proteins, with some more folded than others.525”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [525] source
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PremisecitationThis bias implies centrosomal proteins adopt an ensemble of disordered and partially helical conformations, with helical conformations stabilized upon complex formation depending on pH and concentration.
“This bias implies that they adopt an ensemble of disordered and partially helical conformations, with the latter becoming stabilized when these proteins form complexes, depending on pH and concentration.527”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [527] source
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PremisecitationWeak complexes often have smaller, more planar interfaces with more polar residues.
“Often, weak complexes have smaller contact area and the interfaces are more planar and with more polar residues,511”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [511] source
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PremisecitationAntibody-antigen interfaces have fewer hot spot residues, but Tyr is a preferred hot spot residue for immunoglobulins.
“Even though antibody-antigen interfaces have fewer hot spot residues,496,518 Tyr is a preferred hot spot residue for immunoglobulins.119a”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationEph-ephrin recognition involves stepwise conformational selection and population shift, with two dynamic salt bridges between EphB4 and Ephrin-B2 contributing to specific recognition.
“Dynamic conformational changes during the Eph-ephrin recognition were found to be stepwise conformational selection and population shift events, with two dynamic salt bridges between EphB4 and Ephrin-B2 contributing to specific recognition.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [514] source
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PremisecitationSome protein associations last for the functional lifetime of the protein, while others are transient and repeatedly form and dissociate.
“Some associations are obligatory where one protein is bound to another throughout its functional lifetime, whereas others are transient, continuously forming and dissociating503–510.”
Quote in the paperNot a substantial claim0 of 8 sources checked- cites [503] source
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- cites [504] source
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- cites [505] source
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- cites [506] source
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- cites [507] source
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- cites [508] source
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- cites [509] source
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- cites [510] source
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May combine two claims.
PremisecitationNidogen-1 interactions with laminin variants indicate conformational ensembles of both individual proteins and the complex, implying different interaction modes through distinct interfaces.
“For example, the interactions of nidogen-1 with laminin variants indicate the existence of a conformational ensemble of both individual proteins and complex, implying different modes of interaction through distinct protein-protein interfaces.522”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [522] source
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PremisecitationCentrosomal proteins are larger than control human proteins and have predicted disordered regions covering 57% of their length versus 39% in the general human proteome.
“Centrosomal proteins tend to be larger than a control set of human proteins, and are rich in predicted disordered regions, which cover 57% of their length, compared to 39% in the general human proteome.526”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [526] source
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PremisecitationEphA4 binds ephrin-A1, ephrin-A2, ephrin-A4, ephrin-A5, and ephrin-B2 with affinities of 1.2 μm, 2.3 μm, 36 nm, 360 nm, and 10.8 μm, respectively, indicating varied ligand selectivity.
“the binding affinities of EphA4 with ephrin-A1, ephrin-A2, ephrin-A4, ephrin-A5, and ephrin-B2 are 1.2 μm, 2.3 μm, 36 nm, 360 nm, and 10.8 μm, respectively,512 indicating varied selectivity towards various ligands.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [512] source
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PremisecitationThis cellular ensemble strategy facilitates variable environmental responses and gain of function in network evolution.
“Such a cellular strategy facilitates variable response to the environment and gain of function in network evolution.535”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [535] source
Not checked in the free run.
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PremisecitationProtein disorder in the centrosome correlates with organism complexity in cell-type number, and disordered regions and phosphorylation contribute to mechanical properties and spatiotemporal regulation.
“Interestingly, protein disorder in the centrosome correlates with complexity with the number of cell types, and the structural heterogeneity conferred by the disordered regions and phosphorylation playing an important role in its mechanical properties and regulation in space and time.528”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [528] source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).
InterpretationreasoningBecause RNA and DNA carry genetic information, protein-RNA/DNA interactions should ensure correct processing of genomic information.
“Since RNA and DNA carry generic information, protein-RNA/DNA interactions should ensure correct processing of genomic information.”
Quote in the paperNot a substantial claim- Rests on an assumption: Protein-protein and protein-RNA/DNA interactions follow the same physico-chemical principles.
- Rests on an assumption: RNA and DNA are dynamic molecules.
May combine two claims.
PremisecitationUnphosphorylated and unbound KID is disordered; pKID-KIX interaction causes cooperative folding and binding, forming two α-helices kinked near the phosphorylated site.
“When unphosphorylated and unbound, KID is disordered. Cooperative folding and binding occur upon pKID–KIX interaction, forming two α-helices kinked near the phosphorylated site.529”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [529] source
Not checked in the free run.
The authors state this as an assumption.
Protein function has been optimized by evolution.
“modulated by function which is optimized by evolution”
The paper relies on this without support.
For a given protein function, the active state is unique while inactive states are not unique.
“The active state of a specific function is a unique state, which is not the case for the inactive states;”
The paper relies on this without support.
Conformational states and dynamics observed in isolated, reconstituted, or computational systems correspond to functionally relevant states in the living cell.
“In the heterogeneous cellular environment, protein conformations including those of symmetric oligomers may differ across time and space.”
The paper relies on this without support.
Macromolecular crowding in cells can be represented by the experimental and simulation crowding models discussed.
“In the cellular environment, the high concentration of macromolecules creates crowding effects.”
The paper relies on this without support.
Antibody variable regions must be flexible to recognize highly diversified targets.
“Antibody variable regions are necessarily flexible to enable recognition of tremendously diversified targets.”
The paper relies on this without support.
Natively disordered proteins can form ordered complexes upon binding their partner.
“Upon binding their partner, natively disordered proteins can form ordered complexes.”
The paper relies on this without support.
Cell-signaling proteins have disproportionately intrinsically unstructured regions.
“Cell-signaling proteins also have disproportionately intrinsically unstructured regions.”
The paper relies on this without support.
Protein-protein and protein-RNA/DNA interactions follow the same physico-chemical principles.
“Protein-protein and protein-RNA/DNA interactions should follow the same physico-chemical principles.”
The paper relies on this without support.
RNA and DNA are dynamic molecules.
“Both RNA and DNA are dynamic molecules.”
The paper relies on this without support.
Protein conformational ensembles correlate with gene regulation.
“Protein conformational ensembles should correlate with gene regulation.”
The paper relies on this without support.
Biomacromolecules are dynamical objects that continuously interconvert between structures of varying energies.
“Biomacromolecules are dynamical objects; they continuously interconvert between structures with varying energies.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Native protein conformations are often described as time-averaged ensembles with Boltzmann-type distributions, especially for IDPs and proteins with IDRs.
“Native conformations of proteins are often described as time averaged ensembles of conformations with Boltzmann-type distributions, especially IDPs and proteins with IDRs100,101.”
From The power and pitfalls of AlphaFold2 for structure prediction beyond rigid globular proteins (2024) · cites this paper as [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Temperature and volume are interchanged in the variable definitions
MinorThe list assigns T to volume and V to temperature, but the paper explicitly defines V as volume earlier in the same section.
“Here Cv and Cp are the heat capacity of the system at constant volume and at constant pressure, and kB, m, T, V and βT is Boltzman constant, mass, volume, temperature, and isothermal compressibility of the system, respectively.”
“X2i=volume (V)”
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Allosteric post-translational modification codes
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Self-citationStructured disorder and conformational selection
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- Authors
- Wei, G., Xi, W., Nussinov, R., & Ma, B.
- Affiliations
- Fudan University (CN)
- Tel Aviv University (IL)
- National Cancer Institute (US)
- Corresponding author
- Wei, Guanghong
- Ma, Buyong
- Venue
- Chemical Reviews
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-01-25
- Volume
- 116
- Issue
- 11
- Pages
- 6516-6551
- ISSN
- 0009-2665 (ISSN-L)
- 1520-6890
- PMC
- PMC6407618
- OpenAlex
- W2265800909
- Semantic Scholar
- deccc9316ec26c52d5390bfa2f621c6e68cebe6c
- Cited by
- 436
- References
- 585
- Citations by year
- 2026: 57 · 2025: 48 · 2024: 34 · 2023: 42 · 2022: 43 · 2021: 42 · 2020: 36 · 2019: 45 · 2018: 33 · 2017: 35 · 2016: 20
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Chemical Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (HHSN261200800001E)
- National Natural Science Foundation of China (11274075, 91227102)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- protein conformational ensembles, free energy landscape, thermal fluctuations, protein flexibility, intrinsically disordered proteins, multidomain proteins, protein complexes, intracellular crowding, protein-ligand recognition, enzyme catalysis, protein dynamics, replica exchange molecular dynamics, metadynamics, Markov state models
- MeSH terms
- Humans, Markov Chains, Protein Conformation, Proteins, Thermodynamics, Nuclear Magnetic Resonance, Biomolecular, Molecular Dynamics Simulation, Protein Interaction Maps, Intrinsically Disordered Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
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