Lanthanide-binding de novo proteins -
From metal coordination to catalysis
Artificial metalloenzymes combine the reactivity of metal complexes with the selectivity of proteins. They are generated by rational design and can subsequently be optimized for specific chemical reactions by directed evolution. We utilize de novo protein scaffolds, which are designed computationally, as starting points to develop novel catalysts. In addition to applying the artificial metalloenzymes in biocatalysis, we aim to study their molecular structure and mechanism.
We recently established the formation of robust and specific lanthanide-protein complexes based on a computationally designed TIM barrel scaffold, in which the metal ion is directly coordinated by natural amino acids of the protein, resulting in a femtomolar binding affinity. Site-specific lanthanide binding can be observed by enhancing the element-specific luminescence via energy transfer. Building on this work, we now engineer this de novo metalloprotein to generate a versatile biocatalytic platform for synthetically valuable reactions, including stereoselective carbon-carbon bond formations.
*Caldwell, S.J., *Haydon, I.C., Piperidou, N., Huang, P.S., Bick, M.J., Sjöström, H.S., Hilvert, D., Baker, D., Zeymer, C. (2020) "Tight and specific lanthanide binding in a de novo TIM barrel with a large internal cavity designed by symmetric domain fusion", Proc. Natl. Acad. Sci. U.S.A. 117, 30362-30369