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?Multiagent? Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations
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DOI：10.1021/acssynbio.2c00136.png)
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Enzyme evolution has enabled numerous advances in biotechnology and synthetic biology, yet still requires manyiterative rounds of screening to identify optimal mutant sequences.This is due to the sparsity of thefitness landscape, which is causedby epistatic mutations that only offer improvements whencombined with other mutations. We report an approach thatincorporates diverse substrate analogues in the screening process,where multiple substrates act like multiple agents navigating thefitness landscape, identifying epistatic mutant residues without aneed for testing the entire combinatorial search space. We initiallyvalidate this approach by engineering a malonyl-CoA synthetaseand identify numerous epistatic mutations improving activity forseveral diverse substrates. The majority of these mutations would have been missed upon screening for a single substrate alone. Weexpect that this approach can accelerate a wide array of enzyme engineering programs
Keyword:
enzyme engineering
directed evolution
screening
multiagent
search
fitness landscape
malonyl-CoA
synthetase
epistasis
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