Prediction of the water content in protein binding sites

J Phys Chem B. 2009 Oct 8;113(40):13337-46. doi: 10.1021/jp9047456.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Cattle
  • Computer Simulation*
  • Cyclooxygenase 2 / chemistry
  • Hydro-Lyases / chemistry
  • Lactoglobulins / chemistry
  • Models, Molecular
  • Neuraminidase / chemistry
  • Protein Binding
  • Proteins / chemistry*
  • Solvents
  • Thermodynamics
  • Water / chemistry*

Substances

  • Lactoglobulins
  • Proteins
  • Solvents
  • major urinary proteins
  • Water
  • Cyclooxygenase 2
  • Neuraminidase
  • Hydro-Lyases
  • scytalone dehydratase