title: Modeling water molecules in protein-ligand docking using GOLD.
abstract: We implemented a novel approach to score water mediation and displacement in the protein-ligand docking program GOLD. The method allows water molecules to switch on and off and to rotate around their three principal axes. A constant penalty, sigma(p), representing the loss of rigid-body entropy, is added for water molecules that are switched on, hence rewarding water displacement. We tested the methodology in an extensive validation study. First, sigma(p) is optimized against a training set of 58 protein-ligand complexes. For this training set, our algorithm correctly predicts water mediation/displacement in approximately 92% of the cases. We observed small improvements in the quality of the predicted binding modes for water-mediated complexes. In the second part of this work, an entirely independent set of 225 complexes is used. For this test set, our algorithm correctly predicts water mediation/displacement in approximately 93% of the cases. Improvements in binding mode quality were observed for individual water-mediated complexes.
authors.affiliation: Astex Therapeutics Ltd, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, UK. m.verdonk@astex-therapeutics.com
authors.forename: Marcel L
authors.initials: ML
authors.lastname: Verdonk
authors.forename: Gianni
authors.initials: G
authors.lastname: Chessari
authors.forename: Jason C
authors.initials: JC
authors.lastname: Cole
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hartshorn
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Murray
authors.forename: J Willem M
authors.initials: JW
authors.lastname: Nissink
authors.forename: Richard D
authors.initials: RD
authors.lastname: Taylor
authors.forename: Robin
authors.initials: R
authors.lastname: Taylor
mesh_terms: D000465:Algorithms; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D008024:Ligands; D008074:Lipoproteins / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013937:Thymidine Kinase / Q000737:chemistry; D014867:Water / Q000737:chemistry*
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D008024:Ligands; D008074:Lipoproteins; D011506:Proteins; C046506:oligopeptide-binding protein, bacteria; D014867:Water; D013937:Thymidine Kinase; D015951:Factor Xa; D016333:HIV Protease