PROTON AND HYDRIDE TRANSFERS IN SOLUTION - HYBRID QM MM FREE-ENERGY PERTURBATION STUDY/

A hybrid quantum and molecular mechanical (QM/MM) free energy perturba tion (FEP) method is implemented in the context of molecular dynamics (RID). The semiempirical quantum mechanical (QM) Hamiltonian (Austin M odel 1) represents solute molecules, and the molecular mechanical (MM) CHARMM force field describes the water solvent. The QM/MM FEP method is used to calculate the free energy changes in aqueous solution for ( 1) a proton transfer from methanol to imidazole and (2) a hydride tran sfer from methoxide to nicotinamide. The QM/MM interaction energies be tween the solute and solvent are calibrated to emulate the solute-solv ent interaction energies determined at the Hartee-Fock 6-31G(d) level of ab initio theory. The free energy changes for the proton and hydrid e transfers are calculated to be 15.1 and -6.3 kcal/mol, respectively, which compare favorably with the corresponding experimental values of 12.9 and -7.4 kcal/mol. An estimate of the reliability of the calcula tions is obtained through the computation of the forward (15.1 and -6. 3 kcal/mol) and backward (-14.1 and 9.1 kcal/mol) free energy changes. The reasonable correspondence between these two independent calculati ons suggests that adequate phase space sampling is obtained along the reaction pathways chosen to transform the proton and hydride systems b etween their respective reactant and product states.