Development and Application of Combined Quantum Mechanical and Molecular Mechanical Methods

Compromising of computational cost and accuracy, combined quantum mechanical and molecular mechanical (QM/MM) methods are practical methods for studying large molecular systems. The use of induced dipole polarizable force fields can significantly improve the accuracy of MM and QM/MM methods. However, induced dipole models tend to overestimate the polarization energy at short interaction distances. Damping functions can be applied to reduce the over polarization. MM-MM damping schemes have been developed to correct the overestimated polarization between MM atoms; QM-MM damping scheme has not been developed. In this thesis, a QM-MM damping scheme is developed for the damping of the MM dipole polarizability when the MM atoms are in short interacting distance with QM atoms. With this damping scheme, the induced dipole polarization energies in QM/MM calculation can reproduce the values from accurate QM calculations. A general protocol for applying QM/MM methods to study enzyme catalysis is established, and applied to compute the activation free energy of the hydrogen abstraction reaction of camphor catalyzed by cytochrome enzyme P450cam. The estimated activation free energy is in good agreement with the experiments and the results obtained from other QM/MM methods. Advisor: Hui L