Evaluation of a knowledge-based potential of mean force for scoring docked protein–ligand complexes

Authors

  • Irene Nobeli,

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, University College, Gower Street, London, WC1E 6BT, UK
    • Department of Biochemistry and Molecular Biology, University College, Gower Street, London, WC1E 6BT, UK
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  • John B. O. Mitchell,

    1. Department of Chemistry, University College, London, Gordon Street, WC1H 0AJ, UK
    Current affiliation:
    1. Department of Chemistry, University of Cambridge, Censfield Road, Cambridge CB2 1EW, UK
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  • Alexander Alex,

    1. Molecular Informatics, Structure and Design, Pfizer Global Research and Development, Pfizer Ltd., Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
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  • Janet M. Thornton

    1. Department of Biochemistry and Molecular Biology, University College, Gower Street, London, WC1E 6BT, UK
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Abstract

The Biomolecular Ligand Energy Evaluation Protocol (BLEEP) is a knowledge-based potential derived from high-resolution X-ray structures of protein–ligand complexes. The performance of this potential in ranking the hypothetical structures resulting from a docking study has been evaluated using fifteen protein–ligand complexes from the Protein Data Bank. In the majority of complexes BLEEP was successful in identifying the native (experimental) binding mode or an alternative of low rms deviation (from the native) as the lowest in energy. Overall BLEEP is slightly better than the DOCK energy function in discriminating native-like modes. Even when alternative binding modes rank lower than the native structure, a reasonable energy is assigned to the latter. Breaking down the BLEEP scores into the atom–atom contributions reveals that this type of potential is grossly dominated by longer range interactions (>5 Å), which makes it relatively insensitive to small local variations in the binding site. However, despite this limitation, the lack, at present, of accurate protein–ligand potentials means that BLEEP is a promising approach to improve the filtering of structures resulting from docking programs. Moreover, BLEEP should improve with the continuously increasing number of complexes available in the PDB. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 673–688, 2001

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