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"Multiagent" Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations.

Publication ,  Journal Article
Yang, T; Ye, Z; Lynch, MD
Published in: ACS synthetic biology
May 2022

Enzyme evolution has enabled numerous advances in biotechnology and synthetic biology, yet still requires many iterative rounds of screening to identify optimal mutant sequences. This is due to the sparsity of the fitness landscape, which is caused by epistatic mutations that only offer improvements when combined with other mutations. We report an approach that incorporates diverse substrate analogues in the screening process, where multiple substrates act like multiple agents navigating the fitness landscape, identifying epistatic mutant residues without a need for testing the entire combinatorial search space. We initially validate this approach by engineering a malonyl-CoA synthetase and identify numerous epistatic mutations improving activity for several diverse substrates. The majority of these mutations would have been missed upon screening for a single substrate alone. We expect that this approach can accelerate a wide array of enzyme engineering programs.

Duke Scholars

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Published In

ACS synthetic biology

DOI

EISSN

2161-5063

ISSN

2161-5063

Publication Date

May 2022

Volume

11

Issue

5

Start / End Page

1971 / 1983

Related Subject Headings

  • Synthetic Biology
  • Mutation
  • Epistasis, Genetic
  • 3102 Bioinformatics and computational biology
  • 3101 Biochemistry and cell biology
  • 0903 Biomedical Engineering
  • 0601 Biochemistry and Cell Biology
  • 0304 Medicinal and Biomolecular Chemistry
 

Citation

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Yang, T., Ye, Z., & Lynch, M. D. (2022). "Multiagent" Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations. ACS Synthetic Biology, 11(5), 1971–1983. https://doi.org/10.1021/acssynbio.2c00136
Yang, Tian, Zhixia Ye, and Michael D. Lynch. “"Multiagent" Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations.ACS Synthetic Biology 11, no. 5 (May 2022): 1971–83. https://doi.org/10.1021/acssynbio.2c00136.
Yang T, Ye Z, Lynch MD. "Multiagent" Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations. ACS synthetic biology. 2022 May;11(5):1971–83.
Yang, Tian, et al. “"Multiagent" Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations.ACS Synthetic Biology, vol. 11, no. 5, May 2022, pp. 1971–83. Epmc, doi:10.1021/acssynbio.2c00136.
Yang T, Ye Z, Lynch MD. "Multiagent" Screening Improves Directed Enzyme Evolution by Identifying Epistatic Mutations. ACS synthetic biology. 2022 May;11(5):1971–1983.
Journal cover image

Published In

ACS synthetic biology

DOI

EISSN

2161-5063

ISSN

2161-5063

Publication Date

May 2022

Volume

11

Issue

5

Start / End Page

1971 / 1983

Related Subject Headings

  • Synthetic Biology
  • Mutation
  • Epistasis, Genetic
  • 3102 Bioinformatics and computational biology
  • 3101 Biochemistry and cell biology
  • 0903 Biomedical Engineering
  • 0601 Biochemistry and Cell Biology
  • 0304 Medicinal and Biomolecular Chemistry