I propose to investigate the chemistry of dioxygen activation at monocopper centers and the subsequent reactions of the Cu-oxygen complexes. Studies will focus on the chemistry of two Cu-containing enzymes that carry out alkyl hydroxylation in the biosynthesis of neurohormones, dopamine beta-monooxygenase (DbetaM) and the peptidylglycine alpha - hydroxylating monooxygenase (PHM) component of the bifunctional peptidylglycine alpha-amidating monooxygenase (PAM) enzyme. Quantum chemical calculations on model systems will examine in atomic detail experimentally proposed and alternative catalytic mechanisms, in order to determine reaction (free) energy profiles and the effects of alternative coordination environments. Molecular orbital analyses will be performed and key electronic and structural features ascertained. The results will be interpreted within the context of DbetaM and PHM catalysis. Condensed-phase redox potentials will be computed in order to assess the thermochemistry of electron transfers, while pKa calculations will provide insight into the stability of competing protonation states (i.e. speciation). Kinetic isotope effects (KIEs) will likewise be determined. The environmental effects of the full DbetaM and PHM proteins on the catalytic mechanisms will then be studied through the application of mixed quantum mechanical/molecular mechanical (QM/MM) methods. All modeling will be carried out in conjunction with parallel experimental studies on synthetic biomimetic models prepared in the Tolman lab, to validate the theory via comparison to experimental data and to prioritize future synthetic efforts to address specific issues that may derive from the modeling of the biosites.
| Hill, Lyndal M R; Gherman, Benjamin F; Aboelella, Nermeen W et al. (2006) Electronic tuning of beta-diketiminate ligands with fluorinated substituents: effects on the O2-reactivity of mononuclear Cu(I) complexes. Dalton Trans :4944-53 |
| Gherman, Benjamin F; Tolman, William B; Cramer, Christopher J (2006) Characterization of the structure and reactivity of monocopper-oxygen complexes supported by beta-diketiminate and anilido-imine ligands. J Comput Chem 27:1950-61 |
