Engineering Metallo-Enzyme Environments for Selective C-H Activation Chemistry

The availability of a versatile catalytic platform to precisely target and functionalize individual C-H bonds in complex organic molecules would revolutionize our synthetic strategies, leading to streamlined routes to high value chemicals and supporting the development of a 'greener' chemical industry. Although an impressive range of C-H functionalizations can be achieved with small transition metal complexes, site selectivity is often determined by features of the substrate, and not by the catalyst. A general approach to achieve the more aspirational 'catalyst controlled' transformations requires molecular recognition elements within the catalyst which: a) allow precise substrate orientation and b) can be tuned to alter selectivity. In principle, these requirements could be perfectly addressed by protein catalysts which can be readily adapted via laboratory evolution. However, enzyme engineering strategies are currently limited to Nature's twenty amino acid alphabet which severely restricts our ability to understand biocatalytic C-H activation processes, and furthermore limits the range of metal co-ordination environments, and thus catalytic activities, that are accessible within proteins.

In this studentship we will exploit advanced protein engineering technology available in our laboratory to install 'chemically programmed' ligands and/or noble metal co-factors into selected enzyme scaffolds, opening new avenues to directly probe and tune biocatalytic C-H functionalization mechanisms. We will subsequently demonstrate that the resulting C-H activation catalysts can be systematically optimized via directed evolution with an expanded genetic code using modern ultra-high throughput screening methods, affording biocatalysts with augmented selectivity/activity profiles. This approach merges the broad range of C-H functionalizations accessible with small molecule catalysts with precise control of selectivity provided by proteins, and thus will have major impacts for sustainable manufacturing across the chemical industry.

This project is perfectly aligned with the 'Catalysis' and 'Chemical Biology and Biological Chemistry' EPSRC research areas.