A MOLECULAR MECHANICS GRID METHOD FOR EVALUATION OF LIGAND-RECEPTOR INTERACTIONS

We present a computational method for prediction of the conformation o f a ligand when bound to a macromolecular receptor. The method is inte nded for use in systems in which the approximate location of the bindi ng site is known and no large-scale rearrangements of the receptor are expected upon formation of the complex. The ligand is initially place d in the vicinity of the binding site and the atomic motions of the li gand and binding site are explicitly simulated, with solvent represent ed by an implicit solvation model and using a grid representation for the bulk of the receptor protein. These two approximations make the me thod computationally efficient and yet maintain accuracy close to that of an all-atom calculation. For the benzamidine/trypsin system, we ra n 100 independent simulations, in many of which the ligand settled int o the low-energy conformation observed in the crystal structure of the complex. The energy of these conformations was lower than and well-se parated from that of others sampled. Extensions of this method are als o discussed. (C) 1995 by John Wiley and Sons, Inc.