COMPUTATIONAL DESIGN AND DIRECTED EVOLUTION
Dr. H. Adrian Bunzel
+44 (0) 117 331 2172
Enzymes, designed by Nature over billions of years of evolution, accelerate their reactions with unequaled efficiency. I am harnessing that power to create novel enzymes by computational design and directed evolution.
Currently, I am introducing new photosensitizer binding sites into existing biocatalysts to afford artificial photocatalytic enzymes (1). Furthermore, I am using experimental and computational methods to dissect the dynamic (2) and electrostatic (3) origins of catalysis in designer enzymes.
(1) Artificial Photocatalytic Enzymes
Satisfying mankind’s energy demand from sustainable sources is one of the key challenges of the 21st century. While Nature solved this challenge by harnessing solar energy with almost perfect efficiency, natural photosystems are highly complex, which limits their applications in artificial systems. I employ design and evolution to create efficient photobiocatalysts by equiping structurally simple – but catalytically proficient – heme-containing proteins with affordable organic photosensitizers. The resulting catalysts will be employed to study photon-induced electron transfer and tailored for solar energy conversion and solar fuel production.
(2) Dynamic Origins of Catalysis in Designer Enzymes
During my PhD with Prof. Donald Hilvert (ETH Zurich), I have improved a computationally designed Kemp eliminase by four orders of magnitude with directed evolution. Comparable to natural enzymes, rate enhancements were almost entirely enthalpic. Surprisingly, evolution introduced an activation heat capacity – resulting in curved Eyring plots – and signaling increased rigidity in the transition state ensemble. I am currently employing molecular dynamics simulations to identify the origins of that effect.
(3) Electrostatic Origins of Catalysis in Designer Enzymes
Bunzel HA; Kries H; Marchetti L; Mittl P; Mulholland A; Hilvert D; Emergence of a negative activation heat capacity during evolution of a computationally designed enzyme; J Am Chem Soc 2019, 141, 11745.
Bunzel HA; Garrabou X; Pott M; Hilvert D.; Speeding up enzyme discovery and engineering with ultrahigh-throughput methods; Curr Opin Struct Biol 2018, 48, 149.