Calculation of relative solvation free energy differences by thermodynamicperturbation method: Dependence of free energy results on simulation length

Molecular dynamics (MD) simulations in conjunction with the thermodynamic c ycle perturbation approach has been used to calculate relative solvation fr ee energies for acetone to acetaldehyde, acetone to pyruvic acid, acetone t o 1,1,1-trifluoroacetone, acetone to 1,1,1-trichloroacetone, acetone to 2,3 -butanedione, acetone to cyclopropanone, and formaldehyde hydrate to formal dehyde. To evaluate the dependence of relative solvation free energy conver gence on MD simulation length and starting configuration two studies were p erformed. Ln the first study, each simulation started from the same well-eq uilibrated configuration and the length was varied from 153 to 1530 ps. Ln the second study, the relative solvation free energy differences were calcu lated starting from three different configurations and using 510 ps of MD s imulation for each mutation. These results clearly indicate that, even for molecules with limited conformational flexibility, a simulation length of 5 10 ps or greater is required to obtain satisfactory convergence and, for th e mutations of large structural changes between reactant and product, such as cyclopropanone to acetone, require much longer simulation lengths to ach ieve satisfactory convergence. These results also show that performing one long simulation is better than averaging results from three shortest simula tions of the same length using different starting conformations. (C) 1999 J ohn Wiley & Sons, Inc.