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dc.contributor.authorMitternacht, Simoneng
dc.contributor.authorBerezovsky, Igor N.eng
dc.date.accessioned2012-02-20T09:52:58Z
dc.date.available2012-02-20T09:52:58Z
dc.date.issued2011-12-08eng
dc.identifier.citationPLoS Computational Biology 7(12): e1002301en
dc.identifier.issn1553-734Xeng
dc.identifier.urihttp://hdl.handle.net/1956/5616
dc.descriptionWhat are the molecular mechanisms of allosteric communication in proteins? We base our analysis on the hypothesis that a folded protein has a number of conformational degrees of freedom, which describe fluctuations around the native conformation and switching from/to functional states. Transitions between the protein states involved in function and its regulation are based on coherent conformational degrees of freedom. Motion of one part of a protein along such a degree of freedom, implies a correlated motion in other parts of the protein. By determining which binding sites are simultaneously affected by the same motion we find sites that are allosterically coupled, i.e. where binding at one site can cause a change in ligand-affinity at another. Leverage coupling, the quantity introduced to measure this type of connection, reflects allosteric communication between different binding sites. We show how it can be used to understand allostery in enzymes of different sizes as well as in large protein complexes such as chaperones. Analysis of leverage coupling provides guidance in targeting native and latent regulatory sites.en
dc.description.abstractConformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effector ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational degrees of freedom can be allosterically connected. We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones. Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites.en
dc.language.isoengeng
dc.publisherPublic Library of Scienceeng
dc.rightsAttribution CC BYeng
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/eng
dc.subjectProtein dynamicseng
dc.subjectProtein structureeng
dc.subjectproteinseng
dc.subjectallosteric regulationeng
dc.subjectAllosteryeng
dc.subjectEnzymeeng
dc.subjectchaperoneseng
dc.subjectNormal mode analysiseng
dc.subjectdockingeng
dc.subjectbinding siteseng
dc.subjectcatalytic siteseng
dc.titleCoherent Conformational Degrees of Freedom as a Structural Basis for Allosteric Communicationeng
dc.typePeer reviewedeng
dc.typeJournal articleeng
dc.subject.nsiVDP::Mathematics and natural science: 400::Basic biosciences: 470eng
dc.rights.holderCopyright 2011 Mitternacht, Berezovsky
dc.type.versionpublishedVersioneng
bora.peerreviewedPeer reviewedeng
bibo.doihttp://dx.doi.org/10.1371/journal.pcbi.1002301eng
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pcbi.1002301


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