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Prediction of the water content in protein binding sites.


ABSTRACT: An efficient molecular simulation methodology has been developed to determine the positioning of water molecules in the binding site of a protein or protein-ligand complex. Occupancies and absolute binding free energies of water molecules are computed using a statistical thermodynamics approach. The methodology, referred to as Just Add Water Molecules (JAWS), features "theta-water" molecules that can appear and disappear on a binding-site grid. Key approximations render the technique far more efficient than conventional free energy simulations. Testing of JAWS on five diverse examples (neuraminidase, scytalone dehydratase, major urinary protein 1, beta-lactoglobulin, and COX-2) demonstrates its accuracy in locating hydration sites in comparison to results from high-resolution crystal structures. Possible applications include aid in refinement of protein crystal structures, drug lead optimization, setup of docking calculations, and simulations of protein-ligand complexes.

SUBMITTER: Michel J 

PROVIDER: S-EPMC2891159 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Prediction of the water content in protein binding sites.

Michel Julien J   Tirado-Rives Julian J   Jorgensen William L WL  

The journal of physical chemistry. B 20091001 40


An efficient molecular simulation methodology has been developed to determine the positioning of water molecules in the binding site of a protein or protein-ligand complex. Occupancies and absolute binding free energies of water molecules are computed using a statistical thermodynamics approach. The methodology, referred to as Just Add Water Molecules (JAWS), features "theta-water" molecules that can appear and disappear on a binding-site grid. Key approximations render the technique far more ef  ...[more]

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