Design and engineering of lanthanide-binding proteins: from de novo metal coordination to catalysis
The chemical and pharmaceutical industry is under increasing pressure to replace traditional chemical catalysis with sustainable biocatalytic approaches. However, it remains a major challenge to develop novel enzymes for chemical reactions beyond nature’s synthetic repertoire. A successful strategy is the development of artificial metalloenzymes, which are designed rationally to combine the catalytic properties of an abiotic metal cofactor with the chiral environment of a protein scaffold that provides stereoselectivity. These systems are genetically encodable and therefore amenable to optimization by directed evolution. This technique mimics natural selection in the laboratory through iterative cycles of mutagenesis and screening. We recently established the formation of specific metal-protein complexes from highly stable, computationally designed protein scaffolds. The metal ions are incorporated by dative anchoring, which exploits direct coordination by natural amino acids of the protein. We now work on turning these de novo metalloproteins into a biocatalytic platform for synthetically valuable reactions, such as stereoselective carbon-carbon bond formations. Specifically, we developed a de novo TIM barrel scaffold with femtomolar affinity for lanthanides, where metal binding can be observed by sensitizing the element-specific luminescence. Lanthanide ions are not only potent Lewis acid catalysts; they also promote photoredox chemistry. Our ongoing work thus focuses on the development of artificial lanthanide enzymes.
Hosted by Professor Sagar Khare