Item

Abstract

This thesis presents work on the hybrid quantum mechanical/molecular mechanical (QM/MM) method, both on development and applications. The main focus was on developing a polarizable embedding scheme using the Drude Oscillator (DO) polarizable force field as MM component, in combination with any QM method. An efficient procedure was implemented to obtain the proper polarization state of the QM and MM parts of the system simultaneously. Further improvements could be achieved by coupling this approach with solvent boundary potentials (BPs) making use of an implicit representation of the distant solvent environment through a polarizable dielectric continuum, which reduces the number of degrees of freedom substantially. The QM/MM-DO/BP implementation covers the generalized solvent boundary potential (GSBP) for molecular dynamics simulations and the solvated macromolecule boundary potential (SMBP) for geometry optimizations. These approaches account for long-range electrostatic interactions in a fully polarizable three-layer QM/MM-DO/BP framework.
Making use of our new code and the recently published polarizable version of the CHARMM force field for proteins, we performed the first QM/MM-DO study of enzymatic reactions with polarizable embedding. This involved resolving several technical issues, with regard to the convergence behavior in systems with many polarizable interacting MM atoms and the treatment of polarization at the QM/MM boundary when cutting a covalent bond. We validated the consistency of our QM/MM-DO model for several small test systems through comparisons with full QM results. The QM/MM-DO computations on the enzymatic reactions in chorismate mutase and p-hydroxybenzoate hydroxylase showed polarization effects on the potential energy barriers of the order of 5 to 20%.
We participated in the development of an intrinsic reaction coordinate (IRC) method capable of tackling large QM/MM systems by using a microiterative approach, in which the IRC treatment is applied to a subset of atoms and the remainder of the environment is relaxed by geometry optimization at every step. The method was shown to work well for suitably chosen IRC subsets. We also participated in the development of a QM/MM free energy method that combines efficient low-level sampling with infrequent high-level energy evaluations in a Dual Hamiltonian Free Energy Perturbation (DH-FEP) approach, the merits of which were demonstrated both for small test systems and for two enzymatic reactions.
On the application side, we performed a standard QM/MM study on the Baeyer-Villiger reaction catalyzed by phenylacetone monooxygenase, with emphasis on the role of the active-site residues. We explored their possible configurations, identified the most relevant of these residues, and addressed the role of an extra water molecule in the active site. We also carried out a less conventional QM/MM application by computing the energy dissipation in aqueous solution of a hot ground state obtained after relaxation from an electronically excited state of a HCN tetramer, in the context of a theoretical study that aimed at establishing a photochemical pathway for the prebiotic synthesis of purines.