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Protein Science (2004), 13:735-751. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Improved side-chain prediction accuracy using an ab initio potential energy function and a very large rotamer library

Ronald W. Peterson, P. Leslie Dutton and A. Joshua Wand

The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

(RECEIVED June 8, 2003; FINAL REVISION October 13, 2003; ACCEPTED October 16, 2003)



Abstract

Accurate prediction of the placement and comformations of protein side chains given only the backbone trace has a wide range of uses in protein design, structure prediction, and functional analysis. Prediction has most often relied on discrete rotamer libraries so that rapid fitness of side-chain rotamers can be assessed against some scoring function. Scoring functions are generally based on experimental parameters from small-molecule studies or empirical parameters based on determined protein structures. Here, we describe the NCN algorithm for predicting the placement of side chains. A predominantly first-principles approach was taken to develop the potential energy function incorporating van der Waals and electrostatics based on the OPLS parameters, and a hydrogen bonding term. The only empirical knowledge used is the frequency of rotameric states from the PDB. The rotamer library includes nearly 50,000 rotamers, and is the most extensive discrete library used to date. Although the computational time tends to be longer than most other algorithms, the overall accuracy exceeds all algorithms in the literature when placing rotamers on an accurate backbone trace. Considering only the most buried residues, 80% of the total residues tested, the placement accuracy reaches 92% for {chi}1, and 83% for {chi}1 + 2, and an overall RMS deviation of 1 Å. Additionally, we show that if information is available to restrict {chi}1 to one rotamer well, then this algorithm can generate structures with an average RMS deviation of 1.0 Å for all heavy side-chains atoms and a corresponding overall {chi}1 + 2 accuracy of 85.0%.

Keywords: side-chain prediction; rotamer library; potential energy function; OPLS parameters; simulated annealing

Reprint requests to: A. Joshua Wand, The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, 1013 Stellar-Chance Laboratories, Philadelphia, PA 19104, USA; e-mail: wand{at}mail.med.upenn.edu; fax: (215) 573-7290.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03250104.


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