Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles
- 12 August 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Chemical Theory and Computation
- Vol. 5 (9), 2486-2502
- https://doi.org/10.1021/ct9001812
Abstract
Allostery describes altered protein function at one site due to a perturbation at another site. One mechanism of allostery involves correlated motions, which can occur even in the absence of substantial conformational change. We present a novel method, “MutInf”, to identify statistically significant correlated motions from equilibrium molecular dynamics simulations. Our approach analyzes both backbone and sidechain motions using internal coordinates to account for the gear-like twists that can take place even in the absence of the large conformational changes typical of traditional allosteric proteins. We quantify correlated motions using a mutual information metric, which we extend to incorporate data from multiple short simulations and to filter out correlations that are not statistically significant. Applying our approach to uncover mechanisms of cooperative small molecule binding in human interleukin-2, we identify clusters of correlated residues from 50 ns of molecular dynamics simulations. Interestingly, two of the clusters with the strongest correlations highlight known cooperative small-molecule binding sites and show substantial correlations between these sites. These cooperative binding sites on interleukin-2 are correlated not only through the hydrophobic core of the protein but also through a dynamic polar network of hydrogen bonding and electrostatic interactions. Since this approach identifies correlated conformations in an unbiased, statistically robust manner, it should be a useful tool for finding novel or “orphan” allosteric sites in proteins of biological and therapeutic importance.Keywords
This publication has 81 references indexed in Scilit:
- Backrub-Like Backbone Simulation Recapitulates Natural Protein Conformational Variability and Improves Mutant Side-Chain PredictionJournal of Molecular Biology, 2008
- A Simple Model of Backbone Flexibility Improves Modeling of Side-chain Conformational VariabilityJournal of Molecular Biology, 2008
- Efficient calculation of configurational entropy from molecular simulations by combining the mutual‐information expansion and nearest‐neighbor methodsJournal of Computational Chemistry, 2008
- Molecular Dynamics Simulation of the Escherichia coli NikR Protein: Equilibrium Conformational Fluctuations Reveal Interdomain Allosteric Communication PathwaysJournal of Molecular Biology, 2008
- Engineering Protein Allostery: 1.05 Å Resolution Structure and Enzymatic Properties of a Na+-activated TrypsinJournal of Molecular Biology, 2008
- Allostery: Absence of a Change in Shape Does Not Imply that Allostery Is Not at PlayJournal of Molecular Biology, 2008
- Markov propagation of allosteric effects in biomolecular systems: application to GroEL–GroESMolecular Systems Biology, 2006
- GROMACS: Fast, flexible, and freeJournal of Computational Chemistry, 2005
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validationJournal of Computational Chemistry, 2002