10-01: Computational enzyme design: a tool for rapidly designing new enzymatic activities

The ability to rapidly and reliably design new enzymes is key to design customized cell factories for the production of novel fuels and chemicals. We will illustrate how recent computational techniques are helping towards this goal and discuss their advantages and limitations. Recent successes achieved by the scientific team at Arzeda have enabled for the first time the de novo design of enzymes with entirely new catalytic sites: using dedicated high-performance computing and algorithms [6], around 100 new enzymes were designed and experimentally proven to catalyze a novel retro-aldol reaction [1,2], a Kemp elimination reaction [3,4] and a bimolecular, stereo-selective Diels-Alder reaction [5]. These results will serve to demonstrate the fantastic possibilities but also challenges of de novo enzyme design. We will also illustrate how the same set of computational tools can be used to rapidly identify and reconfigure existing enzyme to tailor them to specific industrial needs. Arzetta Enzyme Identification™ is a two-pronged approach. First, by screening “in-silico” the large amounts of structural and sequence data available in public databases, it allows the fast discovery of existing enzymes that possess both the necessary catalytic machinery and binding pocket to catalyze the desired reaction. Second, for those enzymes that possess the necessary catalytic machinery but lack an active site compatible with the substrate(s) of interest, Arzeda’s Enzyme Identification™ automatically redesigns and remodels the active site pocket enabling catalysis of the desired reaction. Ranking our predicted candidates, we only assay ~100-200 different sequences for activity.