MINING MINIMA - DIRECT COMPUTATION OF CONFORMATIONAL FREE-ENERGY

We describe a novel, two-step method for directly computing the confor mational free energy of a molecule. In the first step, a finite set of low-energy conformations is identified, and its contribution to the c onfiguration integral is evaluated by a straightforward Monte Carlo te chnique. The method of finding energy minima incorporates certain feat ures of the global-underestimator method and of a genetic algorithm. I n the second step, the contribution to the configuration integral due to conformations not included in the initial integration is determined by Metropolis Monte Carlo sampling. Applications to alanine oligopept ides and to three cyclic urea inhibitors of HIV protease are presented .