Design-Evolution Synergy Enables New-to-Nature Enzyme Chemistry
Li, Z.-Q.; Zhang, R. K.; Xie, P.-P.; Kelly, J.; Zhang, Y.; Qin, Z.-Y.; Lambert, T.; Mukhopadhyay, O.; Hanley, D.; Danson, A. E.; Abramson, J.; Singh, S.; Wu, Z.; Kohli, P.; Liu, P.; Wang, J.; Arnold, F. H.
Show abstract
Directed evolution and machine-learning-assisted evolution have transformed biocatalysis by enabling rapid optimisation of catalytic performance within compatible protein scaffolds. In parallel, advances in deep-learning-driven de novo protein design have expanded accessible protein architectural space, enabling the generation of functional catalysts for increasingly challenging transformations. We herein report a synergistic design-evolution strategy to encode new-to-nature regio- and enantioselective C-H amination reactions using engineered de novo haemproteins to synthesise chiral piperidines, a privileged pharmacophore in drug discovery. By integrating motif scaffolding, computational re-design, and directed evolution, we demonstrate de novo enzyme design can enable challenging, high-energy-barrier enzyme chemistry with programmable regio- and enantioselectivity, high catalytic efficiency, excellent enzyme stability, and scaffold diversity.
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