Coherent Conformational Degrees of Freedom as a Structural Basis for Allosteric Communication
TypePeer reviewed; Journal article
MetadataShow full item record
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.
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.
CitationPLoS Computational Biology 7(12): e1002301
PublisherPublic Library of Science
SubjectProtein dynamicsProtein structureproteinsallosteric regulationAllosteryEnzymechaperonesNormal mode analysisdockingbinding sitescatalytic sites
Copyright 2011 Mitternacht, Berezovsky