Interactions in native binding sites cause a large change in protein dynamics

Journal of Molecular Biology
Dengming Ming, Michael E Wall

Abstract

Cellular functions are regulated by molecules that interact with proteins and alter their activities. To enable such control, protein activity, and therefore protein conformational distributions, must be susceptible to alteration by molecular interactions at functional sites. Here we investigate whether interactions at functional sites cause a large change in the protein conformational distribution. We apply a computational method, called dynamics perturbation analysis (DPA), to identify sites at which interactions have a large allosteric potential D(x), which is the Kullback-Leibler divergence between protein conformational distributions with and without an interaction. In DPA, a protein is decorated with surface points that interact with neighboring protein atoms, and D(x) is calculated for each of the points in a coarse-grained model of protein vibrations. We use DPA to examine hundreds of protein structures from a standard small-molecule docking test set, and find that ligand-binding sites have elevated values of D(x): for 95% of proteins, the probability of randomly obtaining values as high as those in the binding site is 10(-3) or smaller. We then use DPA to develop a computational method to predict functional sites in pr...Continue Reading

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Citations

Sep 30, 2009·Chemical Reviews·Ivet BaharIndira H Shrivastava
Oct 14, 2008·The Journal of Pharmacology and Experimental Therapeutics·Spencer S EricksenJohn A Schetz
Oct 26, 2012·BMC Bioinformatics·Alejandro Panjkovich, Xavier Daura
Apr 11, 2007·BMC Bioinformatics·Ying WeiMary Jo Ondrechen
May 27, 2010·BMC Structural Biology·Gareth Williams
Feb 1, 2008·BMC Structural Biology·Dengming MingMichael E Wall
Mar 7, 2012·PloS One·Karin M VerspoorMichael E Wall
Oct 28, 2011·The Journal of Chemical Physics·Ali Rana AtilganCanan Atilgan
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Dec 13, 2016·Journal of Molecular Graphics & Modelling·Shana Bergman, Timothy R Lezon

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