A GENETIC ALGORITHM-BASED METHOD FOR DOCKING FLEXIBLE MOLECULES

We describe a computational method for docking flexible molecules into protein binding sites. The method uses a genetic algorithm (GA) to se arch the combined conformation/orientation space of the molecule to fi nd low energy conformations. Several techniques are described that inc rease the efficiency of the basic search method. These include the use of several interacting GA subpopulations or niches; the use of a ''gr owing'' algorithm that initially dooks only a small part of the molecu le, and the use of gradient minimization during the search. To illustr ate the method, we dock Cbz-GlyP-Leu-Leu (ZGLL) into thermolysin. This system was chosen because a well refined crystal structure is availab le and because another docking method had previously been tested on th is system. Our method is able to find conformations that lie physicall y close to and in some cases lower in energy than the crystal conforma tion in reasonable periods of time on readily available hardware.