De novo design creates enantioselective metalloenzyme photocatalysts

Researchers have used generative protein design and directed evolution to create artificial metalloenzymes that act as highly enantioselective photocatalysts, enabling diverse light-driven reactions with commercially available metal complexes. This breakthrough addresses a long-standing challenge in asymmetric catalysis. The evolved protein scaffolds selectively bind metal polypyridine photocatalysts, which previously could not achieve high enantioselectivity within proteins. Spectroscopic analysis reveals the protein environment extends the photocatalyst's excited-state lifetime and organizes substrates near the cofactor, controlling stereoselectivity and enabling high catalyst turnover and recycling. This work establishes de novo protein design as a viable route to functional scaffolds for synthetic metal complexes lacking natural protein partners, combining computational design with evolution to control non-natural catalytic chemistry. The approach could redefine asymmetric catalysis by imparting selectivity to simple metal catalysts.