De Novo Design of Enantioselective Artificial Metalloenzyme Photocatalysts Containing Metal Polypyridine Cofactors

Abstract

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. In this study, we show that generative protein design can be harnessed to create de novo scaffolds that selectively accommodate one enantiomer of a metal polypyridine photocatalyst as a cofactor. The resulting ArMs enable efficient, enantioselective photocatalysis, highlighting a broadly applicable route for programming stereocontrol into metalloenzyme catalysts. High total turnover numbers are achieved, the ArMs can be recycled by simply extracting reaction products and reusing the aqueous ArM solution for subsequent reactions, and even commercially available racemic cofactor can be used for ArM formation. Transient Absorption characterization revealed that improvements to catalysis result from the increased quantum yield and excited state lifetime of the cofactor upon binding and substrate binding proximal to the cofactor within the ArM active site, which controls reaction stereoselectivity and the mechanism of energy transfer involved in photocatalysis. The simplicity of this approach could help transition ArM research out of a small group of specialist labs to any capable of expressing synthetic genes and working with commercially available metal complexes.