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PEDS Advance Access originally published online on January 9, 2006
Protein Engineering Design and Selection 2006 19(2):55-65; doi:10.1093/protein/gzj001
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Grow to Fit Molecular Dynamics (G2FMD): an ab initio method for protein side-chain assignment and refinement

Wei Zhang1,2 and Yong Duan2,3

1Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716 and 2UC Davis Genome Center and Department of Applied Science, University of California, Davis, CA 95616, USA

3 To whom correspondence should be addressed. E-mail: duan{at}ucdavis.edu

The rough energy landscapes and tight packing of protein interiors are two of the critical factors that have prevented the wide application of physics-based models in protein side-chain assignment and protein structure prediction in general. Complementing the rotamer-based methods, we propose an ab initio method that utilizes molecular mechanics simulations for protein side-chain assignment and refinement. By reducing the side-chain size, a smooth energy landscape was obtained owing to the increased distances between the side chains. The side chains then gradually grow back during molecular dynamics simulations while adjusting to their surrounding driven by the interaction energies. The method overcomes the barriers due to tight packing that limit conformational sampling of physics-based models. A key feature of this approach is that the resulting structures are free from steric collisions and allow the application of all-atom models in the subsequent refinement. Tests on a small set of proteins showed nearly 100% accuracy on both {chi}1 and {chi}2 of buried residues and 94% of them were within 20° from the native conformation, 79% were within 10° and 42% were within 5°. However, the accuracy decreased when exposed side chains were involved. Further improvement and application of the method and the possible reasons that affect the accuracy on the exposed side chains are discussed.

Keywords: G2FMD/Grow to Fit Molecular Dynamics/protein structure/side-chain assignment

Received March 18, 2005; revised October 15, 2005; accepted October 24, 2005.

Edited by Richard Goldstein


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