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Coherent Conformational Degrees of Freedom as a Structural Basis for Allosteric Communication

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dc.contributor.author Mitternacht, Simon
dc.contributor.author Berezovsky, Igor N.
dc.date.accessioned 2012-02-20T09:52:58Z
dc.date.available 2012-02-20T09:52:58Z
dc.date.issued 2011-12-08
dc.identifier.citation PLoS Computational Biology 7(12): e1002301 en
dc.identifier.issn 1553-734X
dc.identifier.uri http://dx.doi.org/10.1371/journal.pcbi.1002301
dc.identifier.uri http://hdl.handle.net/1956/5616
dc.description What 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.abstract Conformational 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.iso eng en
dc.publisher Public Library of Science en
dc.rights Copyright 2011 Mitternacht, Berezovsky en
dc.rights.uri http://creativecommons.org/licenses/by/2.5/ en
dc.subject protein dynamics en
dc.subject protein structure en
dc.subject proteins en
dc.subject allosteric regulation en
dc.subject allostery en
dc.subject enzymes en
dc.subject chaperones en
dc.subject normal mode analysis en
dc.subject docking en
dc.subject binding sites en
dc.subject catalytic sites en
dc.title Coherent Conformational Degrees of Freedom as a Structural Basis for Allosteric Communication en
dc.type Peer reviewed en
dc.type Journal article en
dc.subject.nsi VDP::Mathematics and natural science: 400::Basic biosciences: 470 en
dc.type.version publishedVersion en


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