Nature uses specialized metalloenzymes to carry out small molecule activation reactions, including proton reduction, CO<sub>2</sub> fixation, and O<sub>2</sub> activation, with unparalleled efficiency, rates, and selectivity. Reproducing both the activity and efficiency of metalloenzymes in sustainable anthropogenic systems remains one of the “holy grails” of inorganic chemistry., However, identifying the precise molecular components responsible for these desirable properties has been challenging in the natural metalloenzymes, hindering efforts to develop analogous processes in synthetic compounds. Considering the inherent complexity of a metalloenzyme and the many interactions, both strong and weak, that contribute to the function of an enzyme, we have elected to model natural metalloenzymes on a biochemical platform. Towards this end, we have developed structural, functional, and mechanistic mimics of the [NiFe] hydrogenase, carbon monoxide dehydrogenase (CODH), and acetyl coenzyme A synthase that are based within robust protein scaffolds. Our recent efforts to install and modulate novel reactivity in rubredoxin, ferredoxin, and azurin proteins will be discussed, along with findings from multiple complementary spectroscopic techniques used to probe the catalytic mechanisms. These engineered metalloenzymes provide direct insight into the fundamental chemical principles driving the natural systems and offer design principles for developing catalysts that utilize analogous principles.

Using protein-derived models to study small molecule activation in metalloenzymes: Putting the “bio” in bioinorganic

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.