Efficient electrostatic solvation model for protein-fragment docking

A method is presented for the fast evaluation of the binding energy of a pr otein-small molecule complex with electrostatic solvation. It makes use of a fast preprocessing step based on the assumption that the main contributio n to electrostatic desolvation upon ligand binding originates from the disp lacement of the first shell of water molecules. For a rigid protein, the pr ecomputation of the energy contributions on a set of grids allows the estim ation of the energy in solution of about 300 protein-fragment binding modes per second on a personal computer. The docking procedure is applied to fiv e 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 mi cromolar inhibitors or close analogs are docked and prioritized correctly. The docking based rank-ordering of the library requires about 5 h and is pr oposed as a complementary approach to structure-activity relationships by n uclear magnetic resonance. Proteins 2001;42:256-268. (C) 2000 Wiley-Liss, I nc.