A novel quantum mechanical/molecular mechanical approach to the free energy calculation for isomerization of glycine in aqueous solution

The free energy change associated with the isomerization reaction of glycine in water solution has been studied by a hybrid quantum mechanical/molecular mechanical (QM/MM) approach combined with the theory of energy representation (QM/MM-ER) recently developed. The solvation free energies for both neutral and zwitterionic form of glycine have been determined by means of the QM/MM-ER simulation. The contributions of the electronic polarization and the fluctuation of the QM solute to the solvation free energy have been investigated. It has been found that the contribution of the density fluctuation of the zwitterionic solute is estimated as -4.2 kcalmol in the total solvation free energy of -46.1 kcalmol, while that of the neutral form is computed as -3.0 kcalmol in the solvation free energy of -15.6 kcalmol. The resultant free energy change associated with the isomerization of glycine in water has been obtained as -7.8 kcalmol, in excellent agreement with the experimental data of -7.3 or -7.7 kcalmol, implying the accuracy of the QM/MM-ER approach. The results have also been compared with those computed by other methodologies such as the polarizable continuum model and the classical molecular simulation. The efficiency and advantage of the QM/MM-ER method has been discussed.