Advances in metalloprotein design and engineering: Strategies employed and insights gained

From O₂ generation in photosystem II (PSII) to O₂ reduction in terminal oxidase, from electron transport in plastocyanin to N₂ fixation in nitrogenase, properties of metalloproteins underpin the essentially functions of biology and of life itself. The importance of metalloproteins has only become more apparent over time, and now more than a third of all entries in the Protein Data Bank are metalloproteins.^1,2 Furthermore, the reactions catalyzed by metalloenzymes include many of the most unique and challenging transformations in biology that synthetic coordination complexes cannot yet match. However, despite the relative abundance and significance of metalloproteins, our knowledge of them is lacking when compared to non-metalloproteins. The same synergy between the tunable redox and electronic properties of metal centers and the adaptable bio-coordination spheres around the metal centers in polypeptides that facilitates their functions also gives rise to incredible complexity. This is particularly true in large, multinuclear metalloproteins where the subtle ways by which nature appears to make one plus one equal more than two are extremely difficult to parse. In other chapters of this volume, progress made in understanding structures and functions of these metalloproteins has been summarized. An ultimate test of how much we know about the bio-coordination chemistry of these metalloproteins is to apply that knowledge to design artificial metalloproteins that mimic native proteins in both structure and function. This process would not only confirm what we know but also reveal new subtleties that may have gone overlooked when studying the native enzymes. More importantly, such a....