The DOI matches its Crossref record; 578 of the 585 references it cites were found in a registry or an index; 6 of the 274 sources its claims cite were checked for support.
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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150 Not checked yet · 26 Own interpretation · 16 No basis given · 2 Supported · 2 Own result · 1 Supported so far · 1 Partly supported · accuracy not yet measured
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
What the sources say
- Partly supportedcites [143] sourceExperimental — accuracy not yet measured
The paper reports that a prior survey found hinges near highly frustrated regions, and its 'Rare and Large-Amplitude Fluctuations of Adenylate Kinase' section reports rare motions approaching the opposite state. It does not establish that proximity to high frustration enables those motions; its model comparison attributes them to sequence specificity and nonlinear interactions. The citing sentence also presents the prior survey’s finding as something this paper confirmed. (LLM, conf=0.87)
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Every source the paper cites for this claim was checked and supports it.
In the paper
“These two regions are highly similar to the catalytic regions in MYST-family acetyltransferase Esa1 and Tip60.379”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
What the sources say
- Supportedcites [379] source
The Results section ('Tau acetyltransferase activity is mediated by cysteines') identifies two regions in tau repeats R2 and R3 with approximately 73% sequence homology to the MYST-family acetyltransferases Esa1 and Tip60. The same section identifies a cysteine in each region; the paper also studies these repeats in tau-K18. (LLM, conf=0.94)
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In the paper
“They found that the ensemble model generated reliable responses that match experimental observations.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensembles and molecular machines
What the sources say
- Supportedcites [535] source
The Results (Figure 2, page not specified) report that the ensemble model’s Fus3 dose-response was similar to experimental observations and that simulated G-protein activation followed the pattern seen in experiments. The Results (Parameterization of the model, page not specified) also state that the model replicated these and other experimental observations. (LLM, conf=0.93)
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In the paper
“Cys322 is located in a well-formed helix, which is critical for catalysis.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
What the sources say
- Not checked yetcites [371] source
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In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
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In the paper
“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).”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Introduction
What the sources say
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In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
What the sources say
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- Also stated in: § Intrinsic thermodynamic fluctuation of protein and water · hedged
In the paper
“It is the dynamic change in the distributions – via population shifts – that portrays and captures the linkage to function and life.89”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Introduction
What the sources say
- Not checked yetcites [89] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 8
- It may state two separate claims as one. 61
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Markov state models
What the sources say
- Supportedcites [402] source
Citation 402 is attached to the protein-folding example, not the other applications in the sentence. The Conclusion states that the authors constructed an MSM of ACBP folding, and the Simulation Methods describe building MSMs under folding conditions. (LLM, conf=0.95)
- Supportedcites [403] source
Citation 403 is attached to the protein–ligand binding example, not to the other applications listed. The Results and Discussion describe a Markov state model of benzamidine binding to trypsin, which supports that example. (LLM, conf=0.94)
- Not checked yetcites [404] source
- Supportedcites [405] source
This source supports the protein conformational change example associated with citations 404–405, not every application listed in the sentence. In Results and Discussion, under “Analysis of Conformational Transitions,” the authors build an MSM of HIV-1 protease flap conformations and N-terminal association. (LLM, conf=0.92)
- Not checked yetcites [369] source
- Not checked yetcites [406] source
- Not checked yetcites [407] source
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plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
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In the paper
“One could estimate that the root mean square fluctuations of E and V are respectively:16 〈ΔE2〉≈38kcalmol−1, 〈ΔV2〉≈80Å3.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
What the sources say
- Not checked yetcites [16] source
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
What the sources say
- Not checked yetcites [380] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Introduction
What the sources say
- Not checked yetcites [17] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The statistical energy landscape theory was developed to study protein folding.1,128–131”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Introduction
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
What the sources say
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Introduction
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- The authors state this as an assumption: Protein function has been optimized by evolution.
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In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Introduction
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
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In the paper
“For example, the energy landscape roughness slows down dissociation kinetics and can contribute to streptavidin-biotin interaction dynamic strength.176”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
What the sources say
- Not checked yetcites [176] source
plainconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
What the sources say
- Not checked yetcites [87] source
- Not checked yetcites [88] source
- Not checked yetcites [89] source
- Not checked yetcites [134] source
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“However, long-range contacts in the p53 linker region were required to reproduce the experimental SAXS profile, indicating allosteric communication.227”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-domain proteins with hinge motions or linkers
What the sources say
- Not checked yetcites [227] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“mutations at the hinge regions could allosterically affect the binding-site dynamics or induce alternative binding modes by modifying the ensemble of accessible conformations220.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-domain proteins with hinge motions or linkers
What the sources say
- Not checked yetcites [220] source
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In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Thermodynamic fluctuations and the energy landscape theory
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-domain proteins with hinge motions or linkers
What the sources say
- Not checked yetcites [234] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
- Not checked yetcites [256] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“‘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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: For a given protein function, the active state is unique while inactive states are not unique.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
- Not checked yetcites [259] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-domain proteins with hinge motions or linkers
What the sources say
- Not checked yetcites [234] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“One such example is the p53 protein, which has more than a dozen phosphorylation and acetylation sites with different biological signals.256”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
- Not checked yetcites [256] source
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“The structures of disordered proteins are not ‘random’. Rather, the disordered state has significant metastable structures.240–243,257”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: For a given protein function, the active state is unique while inactive states are not unique.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
- Not checked yetcites [254] source
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The combination of optimal length, IL flexibility, and specific contacts between the IL and interface are needed to stabilize the active state.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-domain proteins with hinge motions or linkers
What the sources say
- Not checked yetcites [236] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-domain proteins with hinge motions or linkers
What the sources say
- Not checked yetcites [235] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Disordered proteins
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control
What the sources say
- Not checked yetcites [412] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
What the sources say
- Not checked yetcites [368] source
boosted- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Markov state models
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Oligomeric proteins with two or more subunits comprise about one third of the cellular proteins,266–267 most of them symmetrical.266”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Structural (and sequence) modules in protein conformational ensembles > Multi-protein complexes
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“IDPs adopt multiple conformations for function;377–378 that is, the multiple conformational ensembles collectively determine functions.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Proteins and their binding partners are flexible and exist in ensembles with certain conformational distributions.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Metadynamics simulations
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Markov state models
plain- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Acetylation of tau inhibits its function and promotes pathological aggregation.373–375”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Experimental and computational methods to characterize protein ensembles > Replica-exchange molecular dynamics simulations
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Molecular dynamics simulations of CypA show that the ensembles of enzyme conformations recognize diverse inhibitors and bind different configurations of the peptide substrate.3”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensemble in enzyme catalysis
What the sources say
- Not checked yetcites [3] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“GPCRs exhibit multiple inactive and active conformations, and the population balance between these conformations is altered upon binding of ligands.415”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-small molecules interactions
What the sources say
- Not checked yetcites [415] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensemble in enzyme catalysis
What the sources say
- Not checked yetcites [449] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-small molecules interactions
What the sources say
- Not checked yetcites [425] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Therefore, receptor activation depends on both low energy states and the range of the conformations sampled by the receptor.416”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-small molecules interactions
What the sources say
- Not checked yetcites [416] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensemble in enzyme catalysis
What the sources say
- Not checked yetcites [468] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-small molecules interactions
What the sources say
- Not checked yetcites [414] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-small molecules interactions
What the sources say
- Not checked yetcites [432] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensemble in enzyme catalysis
What the sources say
- Not checked yetcites [469] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensemble in enzyme catalysis
What the sources say
- Not checked yetcites [442] source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-small molecules interactions
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [523] source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Obviously, the most flexible proteins are the disordered proteins, with some more folded than others.525”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [525] source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [527] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“Often, weak complexes have smaller contact area and the interfaces are more planar and with more polar residues,511”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [511] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Even though antibody-antigen interfaces have fewer hot spot residues,496,518 Tyr is a preferred hot spot residue for immunoglobulins.119a”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [514] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Some associations are obligatory where one protein is bound to another throughout its functional lifetime, whereas others are transient, continuously forming and dissociating503–510.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [522] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [526] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [512] source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Such a cellular strategy facilitates variable response to the environment and gain of function in network evolution.535”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein ensembles and molecular machines
What the sources say
- Not checked yetcites [535] source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [528] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since RNA and DNA carry generic information, protein-RNA/DNA interactions should ensure correct processing of genomic information.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-RNA/DNA interactions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
- 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.
In the paper
“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”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Protein interactions and reactions under ensemble control > Protein-protein recognition
What the sources say
- Not checked yetcites [529] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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?
In the citing paper
“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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
“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.”
§ Protein ensembles: how does nature harness thermodynamic fluctuations for life? > Thermodynamic principle of protein molecules > Intrinsic thermodynamic fluctuation of protein and water
“X2i=volume (V)”
Citations
Cites
Laio, A., & Parrinello, M. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202427399 · Cited by 5,626
Protein folding and misfolding
Dobson, C. M. (2003) · Nature · doi:10.1038/nature02261 · Cited by 4,791
Replica-exchange molecular dynamics method for protein folding
Sugita, Y., & Okamoto, Y. (1999) · Chemical Physics Letters · doi:10.1016/s0009-2614(99)01123-9 · Cited by 4,499
Intrinsically unstructured proteins and their functions
Dyson, H. J., & Wright, P. E. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1589 · Cited by 3,871
Stochastic thermodynamics, fluctuation theorems and molecular machines
Seifert, U. (2012) · Reports on Progress in Physics · doi:10.1088/0034-4885/75/12/126001 · Cited by 3,300
The Energy Landscapes and Motions of Proteins
Frauenfelder, H., Sligar, S. G., & Wolynes, P. G. (1991) · Science · doi:10.1126/science.1749933 · Cited by 3,250
Well-Tempered Metadynamics: A Smoothly Converging and Tunable Free-Energy Method
Barducci, A., Bussi, G., & Parrinello, M. (2008) · Physical Review Letters · doi:10.1103/physrevlett.100.020603 · Cited by 3,184
Funnels, pathways, and the energy landscape of protein folding: A synthesis
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › 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.
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