Proton and Hydride Transfers in Solution: Hybrid QM/MM Free Energy Perturbation Study

Abstract

A hybrid quantum and molecular mechanical (QM/MM) free energy perturbation (FEP) method is implemented in the context of molecular dynamics (MD). The semiempirical quantum mechanical (QM) Hamiltonian (Austin Model 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 transfer from methoxide to nicotinamide. The QM/MM interaction energies between the solute and solvent are calibrated to emulate the solute-solvent interaction energies determined at the Hartee-Fock 6-31G(d) level of ab initio theory. The free energy changes for the proton and hydride 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 calculations 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 calculations suggests that adequate phase space sampling is obtained along the reaction pathways chosen to transform the proton and hydride systems between their respective reactantmore » and product states. 28 refs., 7 figs., 5 tabs.« less