Nature uses barely more than a handful of transition metal ions. Yet, when incorporated into protein scaffolds, this limited set of metal ions carry out innumerable cellular functions and execute essential biochemical transformations such as photochemical H2O oxidation, O2 or CO2 reduction, and N2 fixation, highlighting the outsized importance of metalloproteins in biology. Elucidating the intricate interplay between metal ions and protein structures has been the focus of extensive structural and mechanistic scrutiny over the last several decades. As a result, we have gained a reasonably detailed understanding of how metal ions shape protein structures and how protein structures in turn influence metal reactivity. By contrast, translating this knowledge into an ability to construct functional metalloproteins from scratch remains a great challenge.

Motivated by a desire to (a) build new bioinorganic functions beyond what nature has invented and (b) retrace the routes for the emergence of bioinorganic complexity during evolution, we have developed a design approach in which folded proteins are used as synthons for building supramolecular complexes through metal-mediated self-assembly. The interfaces in the resulting protein superstructures are subsequently tailored with covalent, non-covalent or additional metal-coordination interactions for stabilization and incorporation of new functionalities. This strategy has not only enabled the construction of functional metalloproteins and protein-based materials with unusual properties, but also led to the discovery of fundamental design principles that govern the metal-protein interplay. This presentation will focus on a few examples from our laboratory.