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Efficient electrostatic solvation model for protein-fragment docking

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N. Majeux; M. Scarsi; A. Caflisch

Journal: Proteins
Year: 2001
Volume: 42
Issue: 2
Pages: 256-268
DOI: DOI: 10.1002/1097-0134(20010201)42:2<256::AID-PROT130>3.0.CO;2-4
Type of Publication: Journal Article

Binding Sites; Caspase 1; Ligands; Mitogen-Activated Protein Kinases; Models, Chemical; Models, Molecular; Nuclear Proteins; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Protein Binding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Reproducibility of Results; Software Validation; Static Electricity; Tacrolimus Binding Protein 1A; Thrombin


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.