Life happens in water, and while water is a pretty amazing solvent, it can break down at extreme electrochemial potentials, making catalyzing reactions outside this electrochemical “window” challenging and non-selective. It appears biology never got the message; many enzymes found in all organisms on the planet carry out reduction/oxidation (redox) reactions that stray outside this electrochemical window. We are generally interested in how this is achieved through synergistic properties of enzyme structure, cofactors, and protein dynamics. All redox reactions that occur in this “forbidden territory” require judicious control of electron and proton motion, and thus inspire chemical innovations outside the enzyme active site. Some specific projects of interest are highlighted below.

Phosphorus in biological systems is generally assumed to exist exclusively as the phosphate ion, or phosphoesters thereof, and function solely in acid-base chemistry. Growing evidence suggests that phosphorus redox cycling may be a globally significant process linked to the carbon cycle. We are interested in microbial reduction of phosphate from an energetic, mechanistic, and regulatory perspective. Discoveries in this area have direct implications in the global biogeochemical phosphorus cycle, and may present novel green synthetic routes to reduced phosphorus compounds.

Electron bifurcation is a mechanism of biological energy conservation where electron transfer pathways regulate the flow of electrons in a pairwise manner towards endergonic (energy intensive) and exergonic (energy releasing) branches. While the process has been known for decades, little is understood regarding how bifurcation is controlled, and there are no equivalents in synthetic systems. We are constructing artificial bifurcases in an effort to better understand the molecular design parameters that determine electron bifurcation. Through this “bottom up” approach, elements of bifurcation, including donor-acceptor potentials, spatial distribution, and proton-coupled electron transfer (PCET) dynamics, can be systematically evaluated.

Cysteine thiyl radicals are essential cofactors in a wide range of chemically challenging organic rearrangements, from nucleotide metabolism to glycolysis. Their ubiquity belies our insufficient understanding of their reactivity, particularly how reactivity is tamed within enzyme active sites for high fidelity substrate activation in the presence of numerous off-pathway alternatives. To understand this control we employ newly developed, chemically guided, radical trapping technologies to catch thiyl radicals in the act, and in so doing, provide a point of entry for rational mechanism-based drug design.

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