Protein-based models offer mechanistic insight into complex nickel metalloenzymes.

There are ten nickel enzymes found across biological systems, each with a distinct active site and reactivity that spans reductive, oxidative, and redox-neutral processes. We focus on the reductive enzymes, which catalyze reactions that are highly germane to the modern-day climate crisis: [NiFe] hydrogenase, carbon monoxide dehydrogenase, acetyl coenzyme A synthase, and methyl coenzyme M reductase. The current mechanistic understanding of each enzyme system is reviewed along with existing knowledge gaps, which are addressed through the development of protein-derived models, as described here. This opinion is intended to highlight the advantages of using robust protein scaffolds for modeling multiscale contributions to reactivity and inspire the development of novel artificial metalloenzymes for other small molecule transformations.