GENERAL FORMULATION FOR A QUANTUM FREE-ENERGY PERTURBATION STUDY

We describe a general method whereby ab initio and semiempirical quant um mechanical techniques can be used in free energy perturbation simul ations in which the number of electrons and atoms are being changed. T his involves the introduction of a variable which allows the generatio n of fractional electrons during the course of a free energy perturbat ion simulation. Several applications of this new methodology using the semiempirical PM3 method are presented. These examples demonstrate th at the technique can be successfully utilized to determine free energy differences in the gas phase. Finally, extension of the methodology t o other quantum mechanical approaches and to condensed phases is discu ssed.