Computational studies of the reaction mechanisms and structural determinants of metalloenzymes

Metalloenzymes are crucial in living systems and involve in important functions such as signal-transduction, electron transfer, oxygen metabolism, and cell proliferation and abolition. As a result, clarifying the reaction mechanism and the structural characteristics in the metal-ligand active site are the most important issues. Theoretical calculations, combined with molecular dynamics, are able to study these properties in a greater detail. In this thesis, I applied the theoretical calculations on three important metalloenzymes: Farnesyltransferase (FTase), Ribonuclease H (Rnase H), and Superoxide reductase (SORase). These three enzymes catalyze different reactions. Specifically, FTase catalyzes the transfer of a farnesyl group to proteins belong to Ras superfamily or GTPase, that are involved in cellular signal transduction. We described the enzymatic reaction in atomic detail and determined the possible reaction mechanism in QM/MM simulations. The second system, RNase H enzyme, belongs to the nucleotidyl-transferase superfamily, which involves in the degradation of RNA strands by catalyzing the hydrolysis of the phosphodiester linkage. Here, we introduce a classical molecular dynamics simulation, with modified atomic charges on atoms in the active site, under different concentration of solvated Mg2+ metal ions. The structures showed significant differences in nanosecond trajectories at low and high Mg2+ concentration. The result confirmed the experimental observation, which the activity is inhibited at high concentration of metal ions. The third metalloenzyme SORase is a newly discovered iron-metalloenzyme in anaerobic bacteria and archaea. It shows a high efficiency to convert the toxic superoxide species to hydrogen peroxide. We implemented the Hubbard U correction into the QM/MM calculation to study the spin state of the iron and the metal-ligand coordination configuration in SORase system. A high spin state of Fe2+ ion and a side-on binding conformation of the superoxide were observed in our studies. The results match the experimental data very well. I also calculated the structural, dynamical and electronic properties of the water molecules at air/water interface. Due to the inhomogeneous environment, the molecules on the surface usually possess high reactivity and have unique character. Here, ab initio calculations were applied to study the changes in structure, electronic character, and chemical reactivity at the liquid-vapor interface in the presence of a single fluoride anion