Development and application of the combined quantum mechanical/molecular mechanical method and density functional theory

A new computational approach to studying enzyme reactions based on the combined ab initio quantum mechanical/ molecular mechanical method (QM/MM) has been developed. The key components of the approach are as follows: (1) A pseudobond method has been developed for the treatment of the QM/MM boundary across covalent bonds. This pseudobond method circumvents the major deficiencies of the conventional link atom approach, offers smooth connections between the QM and MM regions, and provides a consistent and well-defined ab initio QM/MM potential energy surface (PES) that can be used for studying enzyme reactions. (2) Based on the pseudobond method, an efficient iterative optimization procedure has been developed to determine optimized structures and minimum energy paths for a system with thousands of movable atoms on the ab initio QM/MM potential energy surface. This procedure allows for the use of ab initio QM/MM method to determine the reaction path with the realistic enzyme environment. (3) With the determined minimum energy paths, free energy perturbation calculations have been carried out to determine the free energy change along the reaction path. With this new QM/MM approach, we have studied the enzyme reaction catalyzed by triosephosphate isomerase. It is found that a low-barrier hydrogen bond (LBHB) is indeed formed in the enediol intermediate, which is short as expected, but the bond strength is less than the 10 to 20 kcal/mol of the LBHB hypothesis.; To enhance the reliability of the quantum mechanical calculations, we have conducted exploratory studies of two challenges for density functional theory: van der Waals interactions and self-interaction error. Counter to the conventional wisdom, it is found that several density functionals based on generalized gradient approximations can provide a good description of binding in the van der Waals systems and that the exchange functional plays a very important role in describing the van der Waals interaction. We have derived a necessary condition for an exchange-correlation functional to be self-interaction free for systems with fractional number of electrons. And we have also developed a new exchange functional to improve the accuracy of DFT methods in describing the atoms and molecules.