DIRECT COMPUTATION OF CONFORMATIONAL FREE ENERGY. Martha S. Head, James
A. Given, Michael K. Gilson. CARB, NIST, Rockville MD 20850. (Building 222,
Room A345, 301-738-6104, email: firstname.lastname@example.org)
Many applications in computational chemistry involve computing the relative stability of different conformational states of a molecular system. In particular, methods for computing the free energy of proteinligand binding are important because of their applicability to computer-aided drug design. We describe a novel, two-step method for directly computing the conformational free energy of a molecule. In the first step, a finite set of low-energy conformations is identified. The contribution of each lowenergy conformation to the configuration integral is evaluated by a straightforward Monte Carlo technique. The method of finding energy minima incorporates certain features of the global underestimator method and of a genetic algorithm. In 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. This method has been used to determine the preferred ring conformations of substituted 5,6dihydroxy cyclic urea inhibitors of HIV1 protease. The conformational preferences presented here are consistent with xray crystallographic and NMR spectroscopic studies of these and related compounds.