title: 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.
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
authors.forename: Julian
authors.initials: J
authors.lastname: Tirado-Rives
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
mesh_terms: D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003198:Computer Simulation; D051546:Cyclooxygenase 2 / Q000737:chemistry; D006836:Hydro-Lyases / Q000737:chemistry; D007782:Lactoglobulins / Q000737:chemistry; D008958:Models, Molecular; D009439:Neuraminidase / Q000737:chemistry; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D012997:Solvents; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D007782:Lactoglobulins; D011506:Proteins; D012997:Solvents; C035737:major urinary proteins; D014867:Water; D051546:Cyclooxygenase 2; D009439:Neuraminidase; D006836:Hydro-Lyases; C082741:scytalone dehydratase