Computational methods for the study of enzymic reaction mechanisms. II. An overlapping mechanically embedded method for hybrid semi-empirical-QM/MM calculations

Semi-empirical quantum mechanics (QM) methods sometimes fail to describe molecular interactions adequately. The description of intermolecular forces, in particular, those associated with strong hydrogen bonding, poses a major problem for the study of protein systems using the semi-empirical AM1 or PM3 methods. Deficiencies in the description of these interactions at the semi-empirical QM level may lead to unphysical proton transfers and, in some instances, cleavage of covalent bonds, due to the large fluctuating forces experienced during molecular dynamics (MD) simulations with QM/MM potentials. In the present work, we describe a simple, computationally efficient and generally applicable method overlapping mechanically embedded (OME) method to overcome these potential problems that may arise with semi-empirical QM-derived forces in the MD. In the OME-QM/MM method, a region is defined in which both QM and MM Hamiltonian terms are computed. Which terms are actually used depends on whether the forces or free energy are being calculated. The method was applied to the calculation of the reaction free energy for the enzymic reduction of DHF by NADPH cofactor found to Escherichia coli dihydrofolate reductase (DHFR). The free energy change for this reduction, calculated using the configuration space sampled in a multiple molecular dynamics (MMD) simulation, was found to be in encouraging agreement, with the experimental results. (C) 2003 Elsevier B.V. All rights reserved.