Matthew Chalkley

Biological systems are able to achieve remarkable transformations using a constrained set of ligands and metals. One mechanism that enzymes use to achieve this is careful control of protons, electrons, and substrate to enable or repurpose reactivity at the active site. I will demonstrate that chemical systems behave similarly. In particular, I show how the chemical identity of the acid and reductant is key to achieving lower overpotential nitrogen fixation catalysis. Under the relevant protic conditions, I evidence that metallocenes are not just electron donors but can also serve as concerted proton-electron transfer (CPET) reagents. Mechanistic understanding of this reactive species gleaned from spectroscopic and thermochemical analysis facilitated design of an improved metallocene-based CPET donor. This enables for the first-time electrochemical nitrogen fixation with a broad range of co-catalysts. Next, I will describe the de novo design of proteins for xeno-biological metallocofactors as a strategy to enhance and control reactivity focusing here on the computational design and experimental validation of a ruthenium cofactor binding protein.

Lastly, I will discuss how cooperative interactions between positron emission tomography (PET) tracers explain the observed binding in the first high-resolution co-structure of a small molecule and an amyloid. Symmetry-matching of these cooperative, non-covalent interactions is key to attaining the structural selectivity observed for the disease-specific binding of diagnostics to amyloid filaments. This novel mechanism offers insight into a structure-based approach to the discovery of new diagnostics and potentially therapeutics for important neurodegenerative diseases such as Alzheimer’s and Parkinson’s.