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Protein-specific force field derived from the fragment molecular orbital method can improve protein–ligand binding interactions

Authors

  • Le Chang,

    1. Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 6068502, Japan
    2. CREST Japan Science and Technology Agency
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  • Takeshi Ishikawa,

    1. Center for Emerging Infectious Diseases, Gifu University, Gifu 5011193, Japan
    2. Graduate School of Engineering, Tohoku University, Sendai 9808579, Japan
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  • Kazuo Kuwata,

    1. CREST Japan Science and Technology Agency
    2. Center for Emerging Infectious Diseases, Gifu University, Gifu 5011193, Japan
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  • Shoji Takada

    Corresponding author
    1. Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 6068502, Japan
    2. CREST Japan Science and Technology Agency
    • Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 6068502, Japan

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Abstract

Accurate computational estimate of the protein–ligand binding affinity is of central importance in rational drug design. To improve accuracy of the molecular mechanics (MM) force field (FF) for protein–ligand simulations, we use a protein-specific FF derived by the fragment molecular orbital (FMO) method and by the restrained electrostatic potential (RESP) method. Applying this FMO-RESP method to two proteins, dodecin, and lysozyme, we found that protein-specific partial charges tend to differ more significantly from the standard AMBER charges for isolated charged atoms. We did not see the dependence of partial charges on the secondary structure. Computing the binding affinities of dodecin with five ligands by MM PBSA protocol with the FMO-RESP charge set as well as with the standard AMBER charges, we found that the former gives better correlation with experimental affinities than the latter. While, for lysozyme with five ligands, both charge sets gave similar and relatively accurate estimates of binding affinities. © 2013 Wiley Periodicals, Inc.

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