FLEXIBLE LIGAND DOCKING WITHOUT PARAMETER ADJUSTMENT ACROSS 4 LIGAND-RECEPTOR COMPLEXES

Understanding molecular recognition is one of the fundamental problems in molecular biology. Computationally, molecular recognition is formu lated as a docking problem. Ideally, a molecular docking algorithm sho uld be computationally efficient, provide reasonably thorough search o f conformational space, obtain solutions with reasonable consistency, and not require parameter adjustments. With these goals in mind, we de veloped DIVALI (Docking with eVolutionary Algorithms), a program which efficiently and reliably searches for the possible binding modes of a ligand within a fixed receptor. We use an AMBER-type potential functi on and search for good ligand conformations using a genetic algorithm (GA). We apply our system to study the docking of both rigid and flexi ble ligands in four different complexes. Our results indicate that it is possible to find diverse binding modes, including structures like t he crystal structure, all with comparable potential function values. T o achieve this, certain modifications to the standard GA recipe are es sential. (C) 1995 by John Wiley & Sons, Inc.