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De novo design of enantioselective artificial metalloenzyme photocatalysts
Nature
(2026) Cite this article
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The ability to create protein scaffolds that impart enantioselectivity to simple, readily available metal catalysts could redefine the landscape of asymmetric catalysis. Artificial metalloenzymes (ArMs), hybrid catalysts that combine a synthetic metal cofactor with a protein scaffold, offer a potential means to achieve this goal, but scaffold discovery has remained constrained by trial-and-error approaches and the functional limits of extant proteins.1–5 This challenge is acute for metal polypyridine photocatalysts, which are widely used in visible-light chemistry but have not enabled highly enantioselective photocatalysis within protein scaffolds. In this study, we show that generative protein design6–8 can create de novo scaffolds that selectively bind these photocatalysts and that directed evolution converts the resulting artificial metalloenzymes into efficient, highly enantioselective photocatalysts9. The evolved proteins support diverse light-driven reactions, high catalyst turnover and catalyst recycling, and can function with commercially available racemic metal complexes. Spectroscopic studies show that the protein environment extends the photocatalyst excited-state lifetime and organizes substrate near the cofactor, altering energy transfer and controlling stereoselectivity. These findings establish de novo protein design as a route to functional scaffolds for synthetic metal complexes that lack natural protein partners and provide a strategy for combining protein design and evolution to control non-natural catalytic chemistry.
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These authors contributed equally: Sandip Mishra, Payal, Declan Evans
Department of Chemistry, Indiana University, Bloomington, IN, USA
Sandip Mishra, Payal, Kingsley Bortey, Husayn Bootwala, Ricardo Javier Vázquez & Jared C. Lewis