SIMULATED ANNEALING ON COUPLED FREE-ENERGY SURFACES - RELATIVE SOLVATION ENERGIES OF SMALL MOLECULES

A method previously presented for sampling coupled potential energy su rfaces and selecting that with the most favorable free energy is exten ded to perform a similar selection on the sum or difference of free en ergies between two states. Whereas the original method is useful for s electing a molecule based on its absolute stability, the new method al lows selection based on its ability to drive a thermodynamic equilibri um, such as binding. Operationally the original method locates the min imum in Delta G(lambda) [lambda couples two chemical compounds], where as the modified version performs the same task on Delta Delta G(lambda ), which is significantly more useful for molecular design strategies. The new algorithm has been tested on the solvation free energy differ ence between methanol and ethane, for which the Delta Delta G was calc ulated to be 6.08 kcal/mol with a barrier of 1.08 or 3.55 kcal/mol (de pending on problem formulation). Simulated annealing was able to rapid ly and routinely locate the most favorable minimum. A significantly mo re challenging artificial problem was also constructed with a calculat ed Delta Delta G of -3.07 kcal/mol and a barrier height of 7.64 kcal/m ol; methods described herein were also able to locate routinely the co rrect minimum in Delta Delta G(lambda) for this problem.