Computational Studies of Organic, Organometallic, and Enzyme Catalysis

Computations are increasingly powerful tools for studying reaction mechanisms and protein catalysis. Various quantum mechanical (QM) and force field-based calculations are applied to problems in organic, organometallic, and protein chemistry. These studies span the chemistry-biology interface, progressing from theoretical studies of gold catalysis, to that of N-heterocyclic carbene (NHC) catalysis, and enzyme catalysis. The first study highlights a gold(I)-catalyzed enyne cyclization with a bifurcating potential energy surface. Several alkynylindoles undergo gold(I)-catalyzed cyclization reactions to form a single isomer in each case. This transformation involves a two-step no-intermediate mechanism with surface bifurcations leading to two or three products. The second gold study is on the mechanism of the rearrangement of acetylenic amine-N-oxides. Further work has been done on the mechanism of the Stetter reaction catalyzed by substituted NHCs. The leucine metabolic pathway was reengineered to produce biofuels, and computations showed that there is push-pull effect between the hydrophobic effect and steric clash, which dictates the LeuA substrate scope. The redesign of a transaminase to install the stereocenter in the blockbuster diabetes drug sitagliptin was attempted. The transaminase that was evolved for the industrial synthesis of sitagliptin, was studied computationally. This study elucidates the energetic details of the transamination mechanism to form sitagliptin, and makes progress toward understanding the role of mutations in the evolution. Finally, a computational, crystallographic, and kinetic study of ketoreductases (KREDs) shows how point mutations change the enantioselectively toward two small substrates, 3-oxa and 3-thiacyclopentanone. QM calculations of the ideal geometry for catalysis, and molecular dynamics (MD) simulations show how small changes in the size, shape, and hydrophobicity of the active site of the enzyme modulate the enantioselectively. Here, we develop an MD method, where simulations are run on the enzyme containing the theozyme for the reduction. This approach probes how well each enzyme stabilizes the transition structures and can predict the experimentally favored enantiomer. Although the subject matter varies, the underlying goal of understanding chemical reactions and catalysis from a physical organic perspective persists