Quantum effects in adenosylcobalamin-dependent enzymes

The ability of radical enzymes to maintain tight control over the high reactive radical intermediates generated in their active sites is not completely understood. In this thesis, we report on a strategy that radical (B12-dependent) enzymes appear to exploit in order to manipulate and control the reactivity of one of their radical intermediate (5'-deoxyadenosyl radical) contained in the active site. The results of quantum mechanical calculations suggest that these enzymes utilize the little known quantum Coulombic effect (QCE), which causes the radical to acquire an electronic structure that contradicts the Aufbau Principle. This effect causes the energy of the singly-occupied molecular orbital (SOMO) of the radical to be well below that of the highest-occupied molecular orbital (HOMO), which renders the radical less reactive. The dynamic nature of the enzyme and its structure is expected to be such that the reactivity of the radical is not restored until it is moved into close proximity of the target substrate. It was found that the enzyme modulates the magnitude of the QCE and consequently reactivity through elaborate manipulation of the hydrogen bonding between 5'-deoxyadenosyl radical and nearby conserved glutamate residue. To the best of our knowledge, this work is the first study suggesting that both classical and quantum electrostatic factors contribute to both the catalytic power of these enzymes, and to the control of the reactivity and selectivity of the radical intermediates. In addition to B12 enzymes this electrostatic paradigm may be employed by other radical enzymes to attain selectivity of hard to control radical reactions.Arts and Sciences, Irving K. Barber School of (Okanagan)Chemistry, Department of (Okanagan)Graduat