Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

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dc.creatorKalescky, Robert
dc.creatorZhou, Hongyu
dc.creatorLiu, Jin
dc.creatorTao, Peng
dc.creator.orcid0000-0002-1067-4063 (Liu, Jin)
dc.date.accessioned2022-09-30T17:34:18Z
dc.date.available2022-09-30T17:34:18Z
dc.date.issued2016-04-26
dc.description.abstractIntra-protein information is transmitted over distances via allosteric processes. This ubiquitous protein process allows for protein function changes due to ligand binding events. Understanding protein allostery is essential to understanding protein functions. In this study, allostery in the second PDZ domain (PDZ2) in the human PTP1E protein is examined as model system to advance a recently developed rigid residue scan method combining with configurational entropy calculation and principal component analysis. The contributions from individual residues to whole-protein dynamics and allostery were systematically assessed via rigid body simulations of both unbound and ligand-bound states of the protein. The entropic contributions of individual residues to whole-protein dynamics were evaluated based on covariance-based correlation analysis of all simulations. The changes of overall protein entropy when individual residues being held rigid support that the rigidity/flexibility equilibrium in protein structure is governed by the La Chatelier's principle of chemical equilibrium. Key residues of PDZ2 allostery were identified with good agreement with NMR studies of the same protein bound to the same peptide. On the other hand, the change of entropic contribution from each residue upon perturbation revealed intrinsic differences among all the residues. The quasi-harmonic and principal component analyses of simulations without rigid residue perturbation showed a coherent allosteric mode from unbound and bound states, respectively. The projection of simulations with rigid residue perturbation onto coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions supporting the population-shift theory of protein allostery. Overall, the study presented here provides a robust and systematic approach to estimate the contribution of individual residue internal motion to overall protein dynamics and allostery.
dc.description.sponsorshipThe authors received no specific funding for this work.
dc.identifier.citationKalescky, R., Zhou, H., Liu, J., & Tao, P. (2016). Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery. PLoS computational biology, 12(4), e1004893. https://doi.org/10.1371/journal.pcbi.1004893
dc.identifier.issn1553-7358
dc.identifier.issue4
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31823
dc.identifier.volume12
dc.publisherPLOS
dc.relation.urihttps://doi.org/10.1371/journal.pcbi.1004893
dc.rights.holder© 2016 Kalescky et al.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourcePLoS Computational Biology
dc.subject.meshAllosteric Regulation
dc.subject.meshComputational Biology
dc.subject.meshComputer Simulation
dc.subject.meshEntropy
dc.subject.meshHumans
dc.subject.meshLigands
dc.subject.meshModels, Molecular
dc.subject.meshMolecular Dynamics Simulation
dc.subject.meshNuclear Magnetic Resonance, Biomolecular
dc.subject.meshPDZ Domains
dc.subject.meshPrincipal Component Analysis
dc.subject.meshProtein Binding
dc.subject.meshProtein Tyrosine Phosphatase, Non-Receptor Type 13 / chemistry
dc.subject.meshProtein Tyrosine Phosphatase, Non-Receptor Type 13 / metabolism
dc.subject.meshProteins / chemistry
dc.subject.meshProteins / metabolism
dc.titleRigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery
dc.typeArticle
dc.type.materialtext

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