Efficient electrostatic solvation model for protein-fragment docking.
A method is presented for the fast evaluation of the binding energy of a protein-small molecule complex with electrostatic solvation. It makes use of a fast preprocessing step based on the assumption that the main contribution to electrostatic desolvation upon ligand binding originates from the displacement of the first shell of water molecules. For a rigid protein, the precomputation of the energy contributions on a set of grids allows the estimation of the energy in solution of about 300 protein-fragment binding modes per second on a personal computer. The docking procedure is applied to five rigid binding sites whose size ranges from 17 residues to a whole protein of 107 amino acids. Using a library of 70 mainly rigid molecules, known micromolar inhibitors or close analogs are docked and prioritized correctly. The docking based rank-ordering of the library requires about 5 h and is proposed as a complementary approach to structure-activity relationships by nuclear magnetic resonance. Proteins 2001;42:256-268.
Majeux
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N
Department of Biochemistry, University of Zürich, Zürich, Switzerland.
Scarsi
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Caflisch
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D001665:Binding Sites; D020170:Caspase 1 / Q000737:chemistry; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000737:chemistry; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2; D015203:Reproducibility of Results; D012986:Software Validation; D055672:Static Electricity; D022061:Tacrolimus Binding Protein 1A / Q000737:chemistry*; D013917:Thrombin / Q000737:chemistry*; D048051:p38 Mitogen-Activated Protein Kinases
D008024:Ligands; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; D020170:Caspase 1; D022061:Tacrolimus Binding Protein 1A