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Configurational-bias sampling technique for predicting side-chain conformations in proteins

¹ Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California 92093-0365, USA
² Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0365, USA
³ Department of Pharmacology, University of California, San Diego, La Jolla, California 92093-0636, USA

(RECEIVED February 15, 2006; FINAL REVISION May 25, 2006; ACCEPTED June 2, 2006)

Prediction of side-chain conformations is an important component of several biological modeling applications. In this work, we have developed and tested an advanced Monte Carlo sampling strategy for predicting side-chain conformations. Our method is based on a cooperative rearrangement of atoms that belong to a group of neighboring side-chains. This rearrangement is accomplished by deleting groups of atoms from the side-chains in a particular region, and regrowing them with the generation of trial positions that depends on both a rotamer library and a molecular mechanics potential function. This method allows us to incorporate flexibility about the rotamers in the library and explore phase space in a continuous fashion about the primary rotamers. We have tested our algorithm on a set of 76 proteins using the all-atom AMBER99 force field and electrostatics that are governed by a distance-dependent dielectric function. When the tolerance for correct prediction of the dihedral angles is a <20° deviation from the native state, our prediction accuracies for ₁ are 83.3% and for ₁ and ₂ are 65.4%. The accuracies of our predictions are comparable to the best results in the literature that often used Hamiltonians that have been specifically optimized for side-chain packing. We believe that the continuous exploration of phase space enables our method to overcome limitations inherent with using discrete rotamers as trials.

Keywords: rotamer library; configurational-bias sampling; side-chain packing; Monte Carlo methods

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