Allostery in Its Many Disguises: From Theory to Applications
Open accessAbstract
Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.
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TL;DR
This review summarizes a CECAM workshop on allostery, integrating computational and experimental perspectives on its mechanistic foundations and practical applications. It highlights ensemble, soft-mode, and dynamic/entropic frameworks while noting that current methods still cannot chart allosteric free-energy landscapes in an unbiased way.
Key findings
- The workshop framed allostery largely through the ensemble/energy-landscape model: allosteric behavior depends on relative stabilities/populations of states, transition timescales/barriers, and ligand/effector binding affinities that remodel the landscape. Soft modes from elastic network models often overlap with ligand-induced conformational changes, and dynamic allostery can arise from entropy/thermal fluctuations without distinct conformational changes, though Nussinov argues only distinct states contribute to functional allostery.
- Mechanistic examples included CRISPR-Cas9, where PAM binding increased correlated motions between HNH and RuvC domains, and mutating K775A and R905A decreased off-target cleavage; GroEL ATP-promoted allosteric transitions were reported as concerted, whereas CCT/TRiC ATP hydrolysis-associated intraring changes were sequential.
- Applications included engineered allosteric switches/sensors using LOV2 and uniRapR domains, chemical rescue of W→G mutants with indole, DNA nanodevices with allosteric control, and computational allosteric-site identification via FTsite and AlloSigMA. Drug-discovery examples mentioned re-sensitizing hepatitis C NS5A variants, HIV integrase inhibitors, PARP-1 allosteric inhibitors, and a PI3Kα mutant-inhibiting site distinct from the active site.
- The workshop involved about 30 computational biophysicists, protein modelers, bioinformaticians, and experimentalists over 2.5 days.
Methods
- This is a meeting report/review of a CECAM workshop, summarizing talks, discussions, and poster contributions; further details are said to be in the Supplemental Information.
- No new primary dataset or systematic analysis is presented; the paper synthesizes cited computational and experimental studies of real protein systems and simple in silico toy materials.
Limitations
- Stated: current computational methods are still unable to chart the free-energy landscape of allosteric systems in an unbiased way, without prior knowledge of significantly populated states; even with such knowledge, methods use varying approximations, making it difficult to evaluate transition-path information.
- Stated: enhanced sampling methods’ potential to yield reliable mechanistic descriptions of allosteric transitions still needs confirmation; MD activation/relaxation protocols have high computational costs and collect only a limited number of transition events.
- Stated: the field would benefit from benchmark allosteric systems with well-characterized active/inactive states, comparison across computational methods, and experimental validation, including phi value-type/LFER analyses; communication-path methods also need more objective benchmarking.
- Evident from the text: as a workshop review, coverage is selective rather than systematic, and no formal quantitative synthesis or risk-of-bias assessment is reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 46 cited sources checked · 0 supported · 0 flagged
- Premisecitation
The intraring conformational changes in CCT/TRiC associated with ATP hydrolysis are sequential.
“A different approach based on an Arrhenius analysis of ATP hydrolysis by the group II chaperonin CCT/ TRiC, the eukaryotic homolog of GroEL, revealed that the intraring conformational changes in this protein associated with ATP hydrolysis are sequential (Gruber et al., 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Gruber et al., 2017 source
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- Interpretationcitation
PAM binding to CRISPR-Cas9 plays a key role in triggering the interdependent conformational dynamics of HNH and RuvC, likely enabling the concerted cleavage of the DNA strands.
“This led the authors to conclude that PAM binding to CRISPR-Cas9 plays a key role in triggering the interdependent conformational dynamics of HNH and RuvC, likely enabling the concerted cleavage of the DNA strands (Palermo et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Palermo et al., 2018 source
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- Premisecitation
The glucocorticoid receptor is able to allosterically regulate function by simultaneously tuning transcriptional activation and repression.
“Investigating the mechanism of transcriptional regulation of the glucocorticoid receptor, a protein involved in signaling whose functionally important N-terminal domain (NTD) is intrinsically disordered, the authors showed that this protein is able to allosterically regulate function by simultaneously tuning transcriptional activation and repression (Li et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Li et al., 2017
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- Interpretationreasoning
The ability to favor such soft modes may have played a role in the evolutionary selection of modules and domains that lend themselves to allosteric regulation.
“suggesting in turn that the ability to favor such soft modes may have played a role in the evolutionary selection of modules and domains that lend themselves to allosteric regulation.”
Quote in the paperNot a substantial claim - Premisecitation
Mutating residues K775A and R905A decreases off-target cleavage of partially complementary DNAs.
“Mutating two of these residues (K775A and R905A) was shown to decrease off-target cleavage of partially complementary DNAs (Chen and Doudna, 2017)”
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- Premisecitation
The conformational changes of proteins elicited by ligand binding closely overlap with one or more of the soft modes accessible in the unbound form.
“Applying ENMs to several systems showed that the conformational changes of proteins elicited by ligand binding closely overlap with one or more of the soft modes accessible in the unbound form (Bahar et al., 2010; Tobi and Bahar, 2005)”
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- cites Tobi and Bahar, 2005
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- Premisecitation
Phi value analysis revealed two parallel pathways for the allosteric transition of GroEL.
“Phi value analysis, shown to be useful for studying protein folding reactions, revealed two parallel pathways for the allosteric transition of this protein (Gruber and Horovitz, 2016).”
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- Premisecitation
Elastic network models have demonstrated the significance of soft collective modes of motion in enabling allosteric regulation of protein systems.
“Bahar and coworkers reviewed approaches based on elastic network models (ENMs), which have demonstrated the significance of soft collective modes of motion in enabling allosteric regulation of protein systems (Bahar et al., 2007, 2017).”
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- cites Bahar et al., 2017
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- Premisecitation
Recent advances in single-molecule techniques and native mass spectrometry make it possible to distinguish between concerted, sequential, or probabilistic conformational changes in multimeric proteins.
“Horovitz showed how recent advances in single-molecule techniques and native mass spectrometry finally made it possible to distinguishing between these models.”
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In silico evolution of elastic toy materials shows that the type of function greatly affects the resulting architectures.
“A surprising result from these in silico experiments is that the type of function greatly affects the resulting architectures.”
Quote in the paperSubstantial claim - Premisecitation
Optimizing networks for a geometric task yields networks displaying a powerful lever at the active site, where the signal is required.
“Optimizing the networks for a geometric task, by selecting network structures where binding a ligand leads to a defined displacement on the other side of the network (“active site”), yields networks displaying a powerful lever at the active site, where the signal is required (Flechsig, 2017; Rocks et al., 2017; Yan et al., 2017a, 2017b).”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisenone given
Using the classical approximation to the harmonic-oscillator partition function yields reasonable estimates of the allosteric free energy between two ligands bound to the allosteron model, which contain no enthalpic terms.
“The author demonstrates that using the classical approximation to the harmonic-oscillator partition function yields reasonable estimates of the allosteric free energy between two ligands bound to such a system, which contain no enthalpic terms.”
Quote in the paperSubstantial claim - Premisenone given
Enhanced sampling algorithms developed in the Bolhuis group require no prior knowledge of the reaction coordinates.
“The advantage of the enhanced sampling algorithms developed in the Bolhuis group is that they require no prior knowledge of the reaction coordinates (the main geometric parameters that change during the reaction process), which is usually not available.”
Quote in the paperNot a substantial claim - Interpretationcitation
The experimental and modeling work by Hilser and colleagues on proteins with intrinsically disordered regions undermines a strict pathway interpretation of allosteric transitions.
“The experimental and modeling work by Hilser and colleagues on proteins with intrinsically disordered regions also undermines a strict pathway interpretation of allosteric transitions.”
Quote in the paperSubstantial claim - Premisecitation
The ATP-promoted allosteric transitions of the homo-heptameric rings of GroEL are concerted.
“Results showed that the ATP-promoted allosteric transitions of the homo-heptameric rings of GroEL are concerted (Dyachenko et al., 2013).”
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- Interpretationcitation
Protein dynamics play an important role in enabling allosteric regulation, as highlighted by computational studies of the CRISPR-Cas9 system.
“The important role of protein dynamics in enabling allosteric regulation was further highlighted by the computational studies of Palermo and McCammon, performed on the large multi-domain CRISPR-Cas9 system”
Quote in the paperSubstantial claim - Premisecitation
Phosphorylation of the RARγ (and RARα) receptors leads to subtle changes in the dynamic properties of the protein without producing significant conformational rearrangements.
“Crystallographic studies of phospho-mimetic mutations of RARγ (S371E) and MD simulations showed that phosphorylation of the RARγ (and RARα) receptors of this family leads to subtle changes in the dynamic properties of the protein without producing significant conformational rearrangements (Chebaro et al., 2013, 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
In thermal fluctuation allostery, soft global modes of motion rather than more local ones are recruited to enable allosteric cooperativity.
“A feature of this mechanism, first formalized by Cooper and Dryden (1984) and termed thermal fluctuations allostery by the author or “dynamic allostery” elsewhere (Guo and Zhou, 2016; Kern and Zuiderweg, 2003; Schueler-Furman and Wodak, 2016, is that soft global modes of motion rather than more local ones are recruited to enable allosteric cooperativity.”
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- cites Guo and Zhou, 2016 source
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- cites Kern and Zuiderweg, 2003
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- Interpretationreasoning
The MD-based activation/relaxation protocol appears as a useful approach for exploring allosteric transitions at atomic resolution in large systems, despite high computational costs and limited number of transition events.
“The MD-based activation/relaxation protocol thus appears as a useful approach for exploring the allosteric transitions at atomic resolution in these large important systems, despite its high computational costs and the fact that it collects only a limited number of transition events.”
Quote in the paperSubstantial claim - Premisecitation
Even in a highly structured protein, "communication" between sites is likely mediated by multiple paths.
“Since even in a highly structured protein “communication” between sites is likely mediated by multiple paths (Guo et al., 2015; Taylor et al., 2016), the questions of whether a given path can be rigorously validated against experimental data, or whether its specific role can be rationalized, need to be critically evaluated.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationcitation
Even when knowledge of significantly populated states is available, computational procedures employ various levels of approximations to sample the conformational transition paths between these states.
“Even when such knowledge is available, computational procedures employ various levels of approximations to sample the conformational transition paths between these states, as illustrated by the contributions of Bulhuis, Faccioli, and Stock, and work of groups employing Markov state models (Chodera and Noe, 2014; Pande et al., 2010).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
MD relaxation of the open form of GluCl upon removal of ivermectin promotes partial closure of the ion pore through a complex quaternary mechanism involving global receptor twisting and radial expansion of the extracellular domain.
“Similarly, MD relaxation of the open form of the eukaryotic glutamate-gated ion channel (GluCl) upon removal of the positive allosteric modulator ivermectin, was shown to promote partial closure of the ion pore through a complex quaternary mechanism involving global receptor twisting and a radial expansion (blooming) of the extracellular domain (Calimet et al., 2013).”
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- Premisecitation
Engineering light-sensitive or ligand-sensitive domains into these sites allows modulation of structural disorder, which affects the active site, switching it between inactive and active states.
“Light or a ligand are then used to modulate structural disorder in these domains, which, in turn, affects the active site of the target protein, switching it between inactive (increased disorder) and active (less disorder) states.”
Quote in the paperSubstantial claim - Premisecitation
Computational procedures can identify solvent-accessible allosteric sites on a target protein.
“The approach consists of using computational procedures to identify solvent-accessible allosteric sites (Proctor et al., 2015) on a target protein and physically engineering naturally occurring light-sensitive or ligand-sensitive domains into these sites.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Proctor et al., 2015 source
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- Premisecitation
A subsequent study of Yifrach and Horovitz (1998) employed a genuine phi value analysis, involving a limited number of mutations, to map the transition state of the allosteric pathway of GroEL.
“A subsequent study of Yifrach and Horovitz (1998) employed a genuine phi value analysis, involving a limited number of mutations, to map the transition state of the allosteric pathway of GroEL.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Yifrach and Horovitz (1998)
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- Interpretationnone given
In many systems, the rate-limiting step of the allosteric transition elicited by effector binding may be governed by the concentration (population) of the pre-existing ligand binding competent state of a protein, rather than by the free-energy barrier of the conformational transition it needs to undergo to adopt this state.
“In many systems, the rate-limiting step of the allosteric transition elicited by effector binding, may indeed be governed by the concentration (population) of the pre-existing ligand binding competent state of a protein, rather than by the free-energy barrier of the conformational transition it needs to undergo to adopt this state.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Fine-tuning the relative populations of the active and inactive states of protein or nucleic acid systems and the binding affinities of allosteric effectors are very effective ways, by nature or in the laboratory, to design systems undergoing allosteric regulation of different levels of complexity and versatility.
“As illustrated here by a number of contributions, fine-tuning the relative populations of the active and inactive states of protein or nucleic acid systems and the binding affinities of allosteric effectors, are very effective ways, by nature or in the laboratory, to design systems undergoing allosteric regulation of different levels of complexity and versatility.”
Quote in the paperNot a substantial claim - Premisecitation
Protein structure and function are most frequently modulated indirectly through control of protein stability.
“A suite of computational and experimental methods, collectively led to the insight that protein structure and function were most frequently modulated indirectly through control of protein stability (Xia et al., 2013).”
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- Interpretationreasoning
The ensemble model of allostery is of very broad applicability.
“The other conceptual framework refers to the so-called ensemble model of allostery, which focuses entirely on the thermodynamic analysis of the energy landscape of allosteric systems, including those featuring intrinsic disorder. It is thus of very broad applicability.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Specific computational approaches depend on the size and complexity of the systems under study, making it difficult to evaluate the information they provide about the identified transition paths.
“Specific approaches depend moreover on the size and complexity of the systems under study, making it difficult to evaluate the information they provide about the identified transition paths.”
Quote in the paperSubstantial claim - Interpretationcitation
Addition of indole in allosteric cases serves not to revert a discrete conformational change, but as an allosteric ligand that rescues activity by inducing the protein to refold to its original conformation.
“Addition of indole in these allosteric cases served not to revert a discrete conformational change, but rather as an allosteric ligand that rescues activity by inducing the protein to refold to its original conformation (Budiardjo et al., 2016)”
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- Premisecitation
A more extended relaxation of GluCl in the absence of ivermectin captured the full closing motion consistent with the ligand-free GluCl X-ray structure.
“A more extended relaxation of the same channel in the absence of ivermectin captured the full closing motion that is consistent with the ligand-free GluCl X-ray structure (Martin et al., 2017).”
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- Premisecitation
The Eaton et al. study validated an earlier computational study, based on a crude analysis of the surface areas buried between the subunits (Janin and Wodak, 1985).
“validating an earlier computational study, based on a crude analysis of the surface areas buried between the subunits (Janin and Wodak, 1985).”
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- Interpretationnone given
Current computational methods are still unable to chart the free-energy landscape of allosteric systems in an unbiased way, without prior knowledge of some significantly populated states of the system.
“Notwithstanding these advances, current computational methods are still unable to chart the free-energy landscape of allosteric systems in an unbiased way, e.g., without prior knowledge of some significantly populated states of the system.”
Quote in the paperSubstantial claim - Premisecitation
The presence of the transcription factor pushes the equilibrium between these states toward the catalytically active one.
“The presence of the transcription factor pushes the equilibrium between these states toward the catalytically active one, in a manner that can be finely controlled further by optimizing the original design (Adornetto et al., 2015).”
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- Premisecitation
Eaton et al. (1991) were the first to apply rate-equilibrium linear free-energy relationships (LFERs) to allostery.
“Eaton et al. (1991) were the first to apply such analyses, generally referred to as rate-equilibrium linear free-energy relationships (LFERs), to allostery.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Eaton et al. (1991) source
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- May combine two claims. 13
- Classified as probably not a substantial claim. 13
- The quote only partly states this claim. 1
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PremisecitationThe main parameters that determine allosteric behavior are the relative stabilities (or populations) of all accessible states, the timescales and energy barriers associated with transitions between states, and the binding affinities of ligands/effectors or conditions.
“The main parameters that determine the allosteric behavior are thus (1) the relative stabilities (or populations) of all the states accessible to the system including those corresponding to active and inactive conformations (with respect to ligand binding for instance), (2) the timescales and energy barriers associated with the transitions between states, and (3) the binding affinities of the lig”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hilser et al., 2012
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- cites Motlagh et al., 2014 source
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InterpretationreasoningThis lever has distinctive structural properties between those of a solid and liquid and may represent a potential candidate mechanism for allosteric proteins in which motion such as opening or closing a channel is required.
“This lever has distinctive structural properties (between those of a solid and liquid) and may represent a potential candidate mechanism for allosteric proteins in which motion such as that for opening or closing a channel is required”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationNon-equilibrium MD simulations of the PDZ2 domain revealed that the structural and dynamic changes undergone by the system are highly non-linear and occur in a non-local fashion, in excellent agreement with experimental data.
“Results revealed that the structural and dynamic changes undergone by the system are highly non-linear and occur in a non-local fashion, in excellent agreement with the experimental data.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Buchenberg et al., 2017
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- cites Stock and Hamm, 2018
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Premiseown dataTo induce cooperativity, the frequency of this mode must adopt moderate values, with the predicted optimal frequency depending on the linear size of the system.
“Crucially, it was found that, to induce cooperativity, the frequency of this mode must adopt moderate values, with the predicted optimal frequency depending on the linear size of the system.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationOptimizing networks for cooperative binding energy yields architectures featuring a very soft elastic mode that extends throughout the structure, with most of the response captured by a single normal mode.
“Completely different architectures evolve when the networks are optimized for cooperative binding energy between the allosteric and active site (Yan et al., 2017a). These evolved architectures feature a very soft elastic mode that extends throughout the structure. In addition, most of the response tends to be captured by a single normal mode, as observed in some allosteric proteins.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yan et al., 2017a
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PremisecitationAllosteric control can be enabled solely through the modulation of thermal fluctuations and the resulting entropy changes, induced by ligand binding.
“McLeish presented work focusing on allosteric control enabled solely through the modulation of thermal fluctuations and the resulting entropy changes, induced by ligand binding.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable). May combine two claims.
InterpretationcitationUnraveling the mechanistic underpinning of allosteric behavior in signaling should lead to improved understanding of how signaling events are relayed and regulated, and enable their modulation with promising pharmaceutical avenues for targeting human disease.
“Unraveling the mechanistic underpinning of this behavior should therefore lead to improved understanding of how signaling events are relayed and regulated, and enable their modulation with promising pharmaceutical avenues for targeting human disease (Dokholyan, 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dokholyan, 2016 source
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- Rests on an assumption: Allosteric behavior of proteins and protein assemblies plays a key role in signaling processes.
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PremisecitationThe ensemble model of allostery holds that the allosteric behavior of a macromolecular system arises from the properties of the native free-energy landscape and how this landscape is remodeled by perturbations such as ligand binding, protonation, or interactions with other proteins.
“According to the ensemble model, first described in the 1980s (Cooper, 1984; Frauenfelder et al., 1988), the allosteric behavior of a macromolecular system arises from the properties of the native free-energy landscape of the system, and how this land-scape is remodeled by various “perturbations,” such as ligand binding, protonation, or interactions with other proteins (Dokholyan, 2016; Kern and Z”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Cooper, 1984
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- cites Frauenfelder et al., 1988
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- cites Dokholyan, 2016 source
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InterpretationreasoningThe two sampling methods (TPS and SCPS) represent important advances, but their potential to yield reliable mechanistic descriptions of the conformational transitions of allosteric systems still needs confirmation.
“The two sampling methods, originally developed to model protein folding/unfolding reactions, represent important advances. But their potential to yield reliable mechanistic descriptions of the conformational transitions of allosteric systems still needs confirmation.”
Quote in the paperNot a substantial claim- Rests on an assumption: The detailed mechanisms whereby the fundamental physical properties underpin allostery are not fully understood.
Classified as probably not a substantial claim. May combine two claims.
InterpretationreasoningThe results of Stock and colleagues led them to propose similarities with downhill protein folding and to question the soundness of interpreting allosteric transitions in terms of well-defined pathways.
“This in turn led the authors to propose similarities with the process of downhill protein folding and to question the soundness of interpreting allosteric transitions in terms of well-defined pathways for propagating the conformational changes, as commonly done in the literature.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.
Interpretationnone givenWe now have a better grasp of the important functional role of protein dynamics and, in particular, the role of protein intrinsic disorder.
“We now have a better grasp of the important functional role of protein dynamics and, in particular, the role of protein intrinsic disorder.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationA synthetic DNA-based nanodevice containing up to four interacting binding sites can load and release a cargo over narrow concentration ranges, and its affinity can be finely controlled via allosteric effectors and environmental cues such as pH and temperature.
“Among the examples used to illustrate the approach was the rational design and engineering of a synthetic DNA-based nanodevice containing up to four interacting binding sites that can load and release a cargo over narrow concentration ranges, and whose affinity could be finely controlled via both allosteric effectors and environmental cues such as pH and temperature (Mariottini et al., 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mariottini et al., 2017
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Premisenone givenSoft modes are estimated computationally from experimental structures, using coarse-grained ENMs, which strongly depend on the reference structure.
“These soft modes are estimated computationally from experimental structures, using coarse-grained ENMs, which strongly depend on the reference structure (usually the experimentally determined one).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPhi value-type analyses measure the changes in the activation energy of unfolding and the free energy of unfolding brought about by mutations, and those are used to characterize the transition states and intermediates of protein folding reactions.
“Such analyses measure the changes in the activation energy of unfolding and the free energy of unfolding brought about by mutations, and those are used to characterize the transition states and intermediates of protein folding reactions (Fersht et al., 1992).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fersht et al., 1992
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Interpretationnone givenComputational procedures and the set of investigated systems for identifying communication paths tend to differ significantly between authors.
“But here, too, computational procedures and the set of investigated systems tend to differ significantly between authors.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenWe also have more powerful computational and experimental tools for sampling significantly populated states of complex protein systems.
“We also have more powerful computational and experimental tools for sampling significantly populated states of complex protein systems.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe concept of allostery has evolved significantly since the first allosteric proteins were characterized.
“The concept of allostery has evolved significantly since the first allosteric proteins were characterized (Motlagh et al., 2014; Schueler-Furman and Wodak, 2016).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Motlagh et al., 2014 source
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- cites Schueler-Furman and Wodak, 2016
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PremisecitationCatalytic DNAzyme sequences combined with consensus sequences recognized by specific transcription factors exhibit either a more stable catalytically inactive conformation unable to bind the cognate transcription factor, or a less-stable conformation competent to bind it.
“In another example, catalytic DNAzyme sequences (e.g., peroxidase-like DNAzymes) were combined with the consensus sequence recognized by specific transcription factors (either TATA binding protein or the microphthalmia-associated transcription factor). The resulting constructs exhibited, respectively, a more stable catalytically inactive conformation unable to bind the cognate transcription factor”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenIdentifying communication paths involves sampling the free-energy landscape only in the vicinity of the stable "end" states, and then quantifying the correlated motions of the corresponding conformational ensembles.
“Although fundamentally different from allosteric transition paths on the free-energy landscape, identifying communication paths also involves sampling the free-energy landscape, but only in the vicinity of the stable “end” states, and then quantifying the correlated motions of the corresponding conformational ensembles.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenAn advantage of allosteric regulation over regulation involving gene expression is its shorter response time to changing conditions.
“An advantage of allosteric regulation over regulation involving gene expression is its shorter response time to changing conditions.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
InterpretationreasoningA conserved long helix plays a key role in mediating the allosteric communication between sites in RARs and likely in other members of the nuclear receptor superfamily where the long helix is well conserved.
“It was furthermore proposed that α conserved long a helix plays a key role in mediating the allosteric communication between sites in these receptors and likely in other members of the nuclear receptor superfamily where the long helix in question is well conserved.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe computational approach presented by Berezovsky can be used to infer allosteric sites and enable the design of effector molecules.
“The computational approach presented by Berezovsky quantifies the configurational work exerted in different parts of a protein as a result of ligand binding to a known or putative allosteric site and can be used to infer allosteric sites, ultimately enabling the design of effector molecules (Guarnera and Berezovsky, 2016a, b).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Guarnera and Berezovsky, 2016a
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- cites Guarnera and Berezovsky, 2016b
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The paper relies on this without support.
Allostery is rooted in the fundamental physical properties of macromolecular systems, and probably of other materials as well.
“Allostery is rooted in the fundamental physical properties of macromolecular systems, and probably of other materials as well.”
The paper relies on this without support.
The detailed mechanisms whereby the fundamental physical properties underpin allostery are not fully understood.
“However, the detailed mechanisms whereby these physical properties underpin allostery are not fully understood.”
The paper relies on this without support.
Allosteric effects are modulated by the cellular context in both health and disease.
“Furthermore, allosteric effects are modulated by the cellular context in both health and disease.”
The paper relies on this without support.
Much remains unknown about the main parameters that determine allosteric behavior.
“However, much remains unknown about these important parameters.”
The paper relies on this without support.
The efficiency of molecular machines is path dependent.
“The efficiency of molecular machines is path dependent.”
The paper relies on this without support.
Allosteric behavior of proteins and protein assemblies plays a key role in signaling processes.
“The allosteric behavior of proteins and protein assemblies plays a key role in signaling processes.”
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?
AlphaFold, which predicts single ranked structures for a protein sequence, is unable to address directly allosteric mechanisms, which are based on populations of conformational states in ensembles.
“AlphaFold, which predicts single ranked structures for a protein sequence, is unable to address directly allosteric mechanisms, which are based on the populations of conformational states in the ensembles.”
From AlphaFold, Artificial Intelligence (AI), and Allostery (2022) · cites this paper as [105]
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Xia, Y., DiPrimio, N., Keppel, T. R., Vo, B., Fraser, K., Battaile, K. P., Egan, C., Bystroff, C., Lovell, S., Weis, D. D., et al. (2013) · Journal of the American Chemical Society · doi:10.1021/ja407644b · Cited by 33 · see citing works
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Adornetto, G., Porchetta, A., Palleschi, G., Plaxco, K. W., & Ricci, F. (2015) · Chemical Science · doi:10.1039/c5sc00228a · Cited by 31 · see citing works
Panecka-Hofman, J., Pöhner, I., Spyrakis, F., et al. (2017) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2017.09.012 · Cited by 28 · see citing works
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Gruber, R., Levitt, M., & Horovitz, A. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1617746114 · Cited by 25 · see citing works
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Self-citation
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The Role of Conformational Dynamics and Allostery in Modulating Protein Evolution
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Allosteric conformational ensembles have unlimited capacity for integrating information
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- Authors
- Wodak, S. J., Paci, E., Dokholyan, N. V., Berezovsky, I. N., Horovitz, A., Li, J., Hilser, V. J., Bahar, I., Karanicolas, J., Stock, G., Hamm, P., Stote, R. H., Eberhardt, J., Chebaro, Y., Dejaegere, A., Cecchini, M., Changeux, J.-P., Bolhuis, P. G., Vreede, J., Faccioli, P., Orioli, S., Ravasio, R., Yan, L., Brito, C., Wyart, M., Gkeka, P., Rivalta, I., Palermo, G., McCammon, J. A., Panecka-Hofman, J., Wade, R. C., Di Pizio, A., Niv, M. Y., Nussinov, R., Tsai, C.-J., Jang, H., Padhorny, D., Kozakov, D., & McLeish, T.
- Affiliations
- VIB-VUB Center for Structural Biology (BE)
- University of Leeds (GB)
- University of North Carolina at Chapel Hill (US)
- Agency for Science, Technology and Research (SG)
- Weizmann Institute of Science (IL)
- Johns Hopkins University (US)
- Fox Chase Cancer Center (US)
- University of Freiburg (DE)
- University of Zurich (CH)
- Institut de génétique et de biologie moléculaire et cellulaire (FR)
- Centre National de la Recherche Scientifique (FR)
- Institut Pasteur (FR)
- University of Amsterdam (NL)
- University of Trento (IT)
- École Polytechnique Fédérale de Lausanne (CH)
- University of California, Santa Barbara (US)
- Universidade Federal do Rio Grande do Sul (BR)
- Sanofi (France) (FR)
- Lyon 1 Université (FR)
- University of California, Riverside (US)
- University of California San Diego (US)
- University of Warsaw (PL)
- Heidelberg University (DE)
- Hebrew University of Jerusalem (IL)
- Tel Aviv University (IL)
- Frederick National Laboratory for Cancer Research (US)
- Stony Brook University (US)
- University of York (GB)
- Corresponding author
- Wodak, Shoshana J.
- ORCID
- Wodak, Shoshana J.
- Paci, Emanuele
- Dokholyan, Nikolay V.
- Berezovsky, Igor N.
- Horovitz, Amnon
- Li, Jing
- Hilser, Vincent J.
- Karanicolas, John
- Stock, Gerhard
- Hamm, Peter
- Stote, Roland H.
- Chebaro, Yassmine
- Dejaegere, Annick
- Cecchini, Marco
- Changeux, Jean-Pierre
- Bolhuis, Peter G.
- Vreede, Jocelyne
- Faccioli, Pietro
- Orioli, Simone
- Ravasio, Riccardo
- Yan, Le
- Brito, Carolina
- Wyart, Matthieu
- Gkeka, Paraskevi
- Rivalta, Ivan
- Palermo, Giulia
- McCammon, J. Andrew
- Panecka-Hofman, Joanna
- Wade, Rebecca C.
- Niv, Masha Y.
- Nussinov, Ruth
- Tsai, Chung-Jung
- Jang, Hyunbum
- Padhorny, Dzmitry
- Kozakov, Dima
- McLeish, Tom
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 27
- Issue
- 4
- Pages
- 566-578
- ISSN
- 0969-2126 (ISSN-L)
- PMC
- PMC6688844
- OpenAlex
- W2911398658
- Cited by
- 404
- References
- 121
- Citations by year
- 2026: 44 · 2025: 57 · 2024: 38 · 2023: 63 · 2022: 67 · 2021: 58 · 2020: 50 · 2019: 26
- FWCI
- 4.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Structure (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc-nd)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- ReIn UW (University of Warsaw) (submittedVersion, cc-by-nc-nd)
- HAL (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- UvA-DARE (University of Amsterdam) (submittedVersion, other-oa)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Centre Européen pour le Calcul Atomic et Moléculaire
- Swiss Industry Science Foundation
- Horizon 2020 (720270)
- NIH (R01GM114015, R01GM064803, R01GM123247, P41GM103712, P30DA035778, NIG GM31749)
- National Cancer Institute
- Center for Cancer Research
- ISF (494/16, 2463/16)
- NSRF
- European Regional Development Fund (09ΣΥN 11-675)
- Marie Curie Reintegration Grant (256533)
- European Commission (INFRA-2010-1.2.3)
- Polish National Science Centre (2016/21/D/NZ1/02806)
- University of Heidelberg
- Klaus Tschira Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- allosteric regulation, protein conformational change, signal transduction, transcriptional regulation, metabolic regulation, macromolecular physics, molecular sensors, drug design
- MeSH terms
- Allosteric Regulation, Allosteric Site, Animals, Gene Expression Regulation, Humans, Proteins, Thermodynamics, Transcription, Genetic, Drug Design, Biosensing Techniques, Signal Transduction, Metabolic Networks and Pathways, Molecular Dynamics Simulation
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 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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