Harnessing molecular symmetry for metalloprotein design

Metalloprotein design has progressed from minimalist strategies that recapitulate only primary coordination spheres to approaches that construct secondary coordination spheres or nonbiological metallocofactors within entirely new metalloprotein scaffolds. In numerous natural systems, active sites often exhibit intrinsic pseudosymmetry or are located at protein-protein interfaces within symmetric assemblies. Inspired by these features, metalloprotein design efforts leverage the inherent molecular symmetry of target metallocofactor-binding sites or homooligomeric protein architectures to achieve precise control over coordination geometry while simplifying the design process and expanding accessible structural and functional complexity. In this Review, we highlight recent advances in artificial metalloproteins that harness molecular symmetry as a central principle to program metalloprotein structure and function, grouped into three distinct strategies.