This dissertation contains simulations of chemical catalysis in both biological and heterogeneous contexts. A mixture of classical, quantum, and hybrid techniques are applied to explore the energy profiles and compare possible chemical mechanisms both within the context of human and bacterial enzymes, as well as exploring surface reactions on a metal catalyst. A brief summary of each project follows. Project 1 — Bacterial Enzyme SpvC The newly discovered SpvC effector protein from Salmonella typhimurium interferes with the host immune response by dephosphorylating mitogen-activated protein kinases (MAPKs) with a -elimination mechanism. The dynamics of the enzyme substrate complex of the SpvC effector is investigated with a 3.2 ns molecular dynamics simulation, which reveals that the phosphorylated peptide substrate is tightly held in the active site by a hydrogen bond network and the lysine general base is positioned for the abstraction of the alpha hydrogen. The catalysis is further modeled with density functional theory (DFT) in a truncated active-site model at the B3LYP/6-31 G(d,p) level of theory. The truncated model suggested the reaction proceeds via a single transition state. After including the enzyme environment in ab initio QM/MM studies, it was found to proceed via an E1cB-like pathway, in which the carbanion intermediate is stabilized by an enzyme oxyanion hole provided by Lys104 and Tyr158 of SpvC. Project 2 — Human Enzyme CDK2 Phosphorylation reactions catalyzed by kinases and phosphatases play an indispensable role in cellular signaling, and their malfunctioning is implicated in many diseases. Ab initio quantum mechanical/molecular mechanical studies are reported for the phosphoryl transfer reaction catalyzed by a cyclin-dependent kinase, CDK2. Our results suggest that an active-site Asp residue, rather than ATP as previously proposed, serves as the general base to activate the Ser nucleophile. The corresponding transition state features a dissociative, metaphosphate-like structure, stabilized by the Mg(II) ion and several hydrogen bonds. The calculated free-energy barrier is consistent with experimental values. Project 3 — Bacterial Enzyme Anthrax Lethal Factor In this dissertation, we report a hybrid quantum mechanical and molecular mechanical study of the catalysis of anthrax lethal factor, an important first step in designing inhibitors to help treat this powerful bacterial toxin. The calculations suggest that the zinc peptidase uses the same general base-general acid mechanism as in thermolysin and carboxypeptidase A, in which a zinc-bound water is activated by Glu687 to nucleophilically attack the scissile carbonyl carbon in the substrate. The catalysis is aided by an oxyanion hole formed by the zinc ion and the side chain of Tyr728, which provide stabilization for the fractionally charged carbonyl oxygen. Project 4 — Methanol Steam Reforming on PdZn alloy Recent experiments suggested that PdZn alloy on ZnO support is a very active and selective catalyst for methanol steam reforming (MSR). Plane-wave density functional theory calculations were carried out on the initial steps of MSR on both PdZn and ZnO surfaces. Our calculations indicate that the dissociation of both methanol and water is highly activated on \ufb02at surfaces of PdZn such as (111) and (100), while the dissociation barriers can be lowered significantly by surface defects, represented here by the (221), (110), and (321) faces of PdZn. The corresponding processes on the polar Zn-terminated ZnO(0001) surfaces are found to have low or null barriers. Implications of these results for both MSR and low temperature mechanisms are discussed.
NSF, NIH, and ACS Petroleum research fund.
Salmonella, Shingella, CDK2, Simulations, Enzyme Catalysis, Chemical Mechanism, Molecular Dynamics, QM/MM, Surface Catalysis, Methanol Steam Reforming, PdZn, plane-wave DFT
Level of Degree
Department of Chemistry and Chemical Biology
First Committee Member (Chair)
Second Committee Member
Third Committee Member
Smith, Gregory K.. "Simulations of Chemical Catalysis." (2014). https://digitalrepository.unm.edu/chem_etds/33