Estimating protein–ligand binding free energy: Atomic solvation parameters for partition coefficient and solvation free energy calculation

Authors

  • Jianfeng Pei,

    1. State Key Laboratory for Structural Chemistry of Stable and Unstable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
    2. Center for Theoretical Biology, Peking University, Beijing, China
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  • Qi Wang,

    1. State Key Laboratory for Structural Chemistry of Stable and Unstable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
    2. Center for Theoretical Biology, Peking University, Beijing, China
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  • Jiaju Zhou,

    1. Institute of Process Engineering, Chinese Academy of Sciences, Beijing, China
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  • Luhua Lai

    Corresponding author
    1. State Key Laboratory for Structural Chemistry of Stable and Unstable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
    2. Center for Theoretical Biology, Peking University, Beijing, China
    • College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
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Abstract

Solvation energy calculation is one of the main difficulties for the estimation of protein–ligand binding free energy and the correct scoring in docking studies. We have developed a new solvation energy estimation method for protein–ligand binding based on atomic solvation parameter (ASP), which has been shown to improve the power of protein–ligand binding free energy predictions. The ASP set, designed to handle both proteins and organic compounds and derived from experimental n-octanol/water partition coefficient (log P) data, contains 100 atom types (united model that treats hydrogen atoms implicitly) or 119 atom types (all-atom model that treats hydrogen atoms explicitly). By using this unified ASP set, an algorithm was developed for solvation energy calculation and was further integrated into a score function for predicting protein–ligand binding affinity. The score function reproduced the absolute binding free energies of a test set of 50 protein–ligand complexes with a standard error of 8.31 kJ/mol. As a byproduct, a conformation-dependent log P calculation algorithm named ASPLOGP was also implemented. The predictive results of ASPLOGP for a test set of 138 compounds were r = 0.968, s = 0.344 for the all-atom model and r = 0.962, s = 0.367 for the united model, which were better than previous conformation-dependent approaches and comparable to fragmental and atom-based methods. ASPLOGP also gave good predictive results for small peptides. The score function based on the ASP model can be applied widely in protein–ligand interaction studies and structure-based drug design. Proteins 2004. © 2004 Wiley-Liss, Inc.

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