Comparison of linear‐scaling semiempirical methods and combined quantum mechanical/molecular mechanical methods for enzymic reactions. II. An energy decomposition analysis

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Abstract
QM/MM methods have been developed as a computationally feasible solution to QM simulation of chemical processes, such as enzyme‐catalyzed reactions, within a more approximate MM representation of the condensed‐phase environment. However, there has been no independent method for checking the quality of this representation, especially for highly nonisotropic protein environments such as those surrounding enzyme active sites. Hence, the validity of QM/MM methods is largely untested. Here we use the possibility of performing all‐QM calculations at the semiempirical PM3 level with a linear‐scaling method (MOZYME) to assess the performance of a QM/MM method (PM3/AMBER94 force field). Using two model pathways for the hydride‐ion transfer reaction of the enzyme dihydrofolate reductase studied previously (Titmuss et al., Chem Phys Lett 2000, 320, 169–176), we have analyzed the reaction energy contributions (QM, QM/MM, and MM) from the QM/MM results and compared them with analogous‐region components calculated via an energy partitioning scheme implemented into MOZYME. This analysis further divided the MOZYME components into Coulomb, resonance and exchange energy terms. For the model in which the MM coordinates are kept fixed during the reaction, we find that the MOZYME and QM/MM total energy profiles agree very well, but that there are significant differences in the energy components. Most significantly there is a large change (∼16 kcal/mol) in the MOZYME MM component due to polarization of the MM region surrounding the active site, and which arises mostly from MM atoms close to (ab initio QM linear‐scaling calculations. Such a force field could be used efficiently in MD simulations to calculate free energies. © 2002 Wiley Periodicals, Inc. J Comput Chem 23: 1314–1322, 2002