title: Evaluation of water displacement energetics in protein binding sites with grid cell theory.
abstract: Excess free energies, enthalpies and entropies of water in protein binding sites were computed via classical simulations and Grid Cell Theory (GCT) analyses for three pairs of congeneric ligands in complex with the proteins scytalone dehydratase, p38α MAP kinase and EGFR kinase respectively. Comparative analysis is of interest since the binding modes for each ligand pair differ in the displacement of one binding site water molecule, but significant variations in relative binding affinities are observed. Protocols that vary in their use of restraints on protein and ligand atoms were compared to determine the influence of protein-ligand flexibility on computed water structure and energetics, and to assess protocols for routine analyses of protein-ligand complexes. The GCT-derived binding affinities correctly reproduce experimental trends, but the magnitude of the predicted changes in binding affinities is exaggerated with respect to results from a previous Monte Carlo Free Energy Perturbation study. Breakdown of the GCT water free energies into enthalpic and entropic components indicates that enthalpy changes dominate the observed variations in energetics. In EGFR kinase GCT analyses revealed that replacement of a pyrimidine by a cyanopyridine perturbs water energetics up three hydration shells away from the ligand.
authors.affiliation: EaStCHEM School of Chemistry, Joseph Black Building, The King's Buildings, Edinburgh, EH9 3JJ, UK. mail@julienmichel.net.
authors.forename: G
authors.initials: G
authors.lastname: Gerogiokas
authors.forename: M W Y
authors.initials: MW
authors.lastname: Southey
authors.forename: M P
authors.initials: MP
authors.lastname: Mazanetz
authors.forename: A
authors.initials: A
authors.lastname: Heifetz
authors.forename: A
authors.initials: A
authors.lastname: Hefeitz
authors.forename: M
authors.initials: M
authors.lastname: Bodkin
authors.forename: R J
authors.initials: RJ
authors.lastname: Law
authors.forename: J
authors.initials: J
authors.lastname: Michel
mesh_terms: D001665:Binding Sites; D066246:ErbB Receptors / Q000737:chemistry* / Q000378:metabolism; D006836:Hydro-Lyases / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009010:Monte Carlo Method; D013816:Thermodynamics; D014867:Water / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D014867:Water; D066246:ErbB Receptors; D048308:Mitogen-Activated Protein Kinase 14; D006836:Hydro-Lyases; C082741:scytalone dehydratase