Prediction of side-chain conformations on protein surfaces

Authors

  • Zhexin Xiang,

    Corresponding author
    1. Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892-5624
    • Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Building 12A Room 2051, 12 South Drive, Bethesda, MD 20892-5624
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  • Peter J. Steinbach,

    1. Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, Maryland 20892-5624
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  • Matthew P. Jacobson,

    1. Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143-2240
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  • Richard A. Friesner,

    1. Department of Chemistry, Columbia University, New York, New York 10027
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  • Barry Honig

    1. Howard Hughes Medical Institute, Center for Computational Biology and Bioinformatics and Department of Biochemistry and Molecular Biophysics, Columbia University, 1130 St. Nicholas Avenue, Room 815, New York, New York 10032
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  • This article is a US Government work and, as such, is in the public domain in the United States of America.

Abstract

An approach is described that improves the prediction of the conformations of surface side chains in crystal structures, given the main-chain conformation of a protein. A key element of the methodology involves the use of the colony energy. This phenomenological term favors conformations found in frequently sampled regions, thereby approximating entropic effects and serving to smooth the potential energy surface. Use of the colony energy significantly improves prediction accuracy for surface side chains with little additional computational cost. Prediction accuracy was quantified as the percentage of side-chain dihedral angles predicted to be within 40° of the angles measured by X-ray diffraction. Use of the colony energy in predictions for single side chains improved the prediction accuracy for χ1 and χ1+2 from 65 and 40% to 74 and 59%, respectively. Several other factors that affect prediction of surface side-chain conformations were also analyzed, including the extent of conformational sampling, details of the rotamer library employed, and accounting for the crystallographic environment. The prediction of conformations for polar residues on the surface was generally found to be more difficult than those for hydrophobic residues, except for polar residues participating in hydrogen bonds with other protein groups. For surface residues with hydrogen-bonded side chains, the prediction accuracy of χ1 and χ1+2 was 79 and 63%, respectively. For surface polar residues, in general (all side-chain prediction), the accuracy of χ1 and χ1+2 was only 73 and 56%, respectively. The most accurate results were obtained using the colony energy and an all-atom description that includes neighboring molecules in the crystal (protein chains and hetero atoms). Here, the accuracy of χ1 and χ1+2 predictions for surface side chains was 82 and 73%, respectively. The root mean square deviations obtained for hydrogen-bonding surface side chains were 1.64 and 1.81 Å, with and without consideration of crystal packing effects, respectively. Proteins 2007. © 2007 Wiley-Liss, Inc.

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