Novel modulation factor quantifies the role of water molecules in protein interactions

Authors

  • Marta Bueno,

    Corresponding author
    1. Department of Pathology, Division of Transplant Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213
    • Department of Pathology, Division of Transplant Pathology, University of Pittsburgh, E732 UPMC-Montefiore Hospital, 3459 Fifth Avenue, Pittsburgh, PA 15260
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  • Nuri A. Temiz,

    1. Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
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  • Carlos J. Camacho

    Corresponding author
    1. Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260
    • Department of Computational and Systems Biology, University of Pittsburgh, 3501 Fifth Avenue, Room 3077, Pittsburgh, PA 15260
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Abstract

Water molecules decrease the potential of mean force of a hydrogen bond (H-bond), as well as modulate (de)solvation forces, but exactly how much has not been easy to determine. Crystallographic water molecules provide snapshots of optimal solutions for the role of solvent in protein interactions, information that is often ignored by implicit solvent models. Motivated by high-resolution crystal structures, we describe a simple quantitative approach to explicitly incorporate the role of molecular water in protein interactions. Applications to protein–DNA interactions show that the accuracy of binding free-energy estimates improves significantly if a distinction is made between H-bonds that are desolvated (or only contact crystal waters), solvated by mobile waters trapped at the binding interface, or partially solvated through connections to bulk water. These different environments are modeled by a unique “water” scaling factor that decreases or increases the strength of hydrogen bonds depending on whether water contacts the acceptor or donor atoms or the bond is fully desolvated, respectively. Our empirical energies are fully consistent with mobile water molecules having a strong polarization effect in direct intermolecular interactions. Proteins 2010. © 2010 Wiley-Liss, Inc.

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