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GRID: A high-resolution protein structure refinement algorithm

Chitsaz, Mohsen and Mayo, Stephen L. (2013) GRID: A high-resolution protein structure refinement algorithm. Journal of Computational Chemistry, 34 (6). pp. 445-450. ISSN 0192-8651. doi:10.1002/jcc.23151.

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The energy-based refinement of protein structures generated by fold prediction algorithms to atomic-level accuracy remains a major challenge in structural biology. Energy-based refinement is mainly dependent on two components: (1) sufficiently accurate force fields, and (2) efficient conformational space search algorithms. Focusing on the latter, we developed a high-resolution refinement algorithm called GRID. It takes a three-dimensional protein structure as input and, using an all-atom force field, attempts to improve the energy of the structure by systematically perturbing backbone dihedrals and side-chain rotamer conformations. We compare GRID to Backrub, a stochastic algorithm that has been shown to predict a significant fraction of the conformational changes that occur with point mutations. We applied GRID and Backrub to 10 high-resolution (≤ 2.8 Å) crystal structures from the Protein Data Bank and measured the energy improvements obtained and the computation times required to achieve them. GRID resulted in energy improvements that were significantly better than those attained by Backrub while expending about the same amount of computational resources. GRID resulted in relaxed structures that had slightly higher backbone RMSDs compared to Backrub relative to the starting crystal structures. The average RMSD was 0.25 ± 0.02 Å for GRID versus 0.14 ± 0.04 Å for Backrub. These relatively minor deviations indicate that both algorithms generate structures that retain their original topologies, as expected given the nature of the algorithms.

Item Type:Article
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Mayo, Stephen L.0000-0002-9785-5018
Additional Information:© 2012 Wiley Periodicals, Inc. Received: 12 April 2012; Revised: 31 July 2012; Accepted: 27 August 2012; Published online on 15 October 2012. The authors would like to thank Marie Ary for her comments and assistance in writing the manuscript. Contract/grant sponsors: Defense Advanced Research Projects Agency (DARPA), Department of Defense National Security Science and Engineering Faculty Fellowship.
Funding AgencyGrant Number
Defense Advanced Research Projects Agency (DARPA)UNSPECIFIED
Department of Defense National Security Science and Engineering Faculty FellowshipUNSPECIFIED
Subject Keywords:protein structure refinement; flexible backbone; energy-based refinement; conformational search; backrub motion
Issue or Number:6
Record Number:CaltechAUTHORS:20130321-144912093
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Official Citation:M. Chitsaz, S. L. Mayo, J. Comput. Chem. 2013, 34, 445–450. DOI: 10.1002/jcc.23151
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:37594
Deposited By: Tony Diaz
Deposited On:25 Mar 2013 23:13
Last Modified:09 Nov 2021 23:30

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