Active learning-assisted directed evolution

Jason Yang, Ravi G. Lal, James C. Bowden, Raul Astudillo, Mikhail A. Hameedi, Sukhvinder Kaur, Matthew Hill, Yisong Yue () and Frances H. Arnold ()
Additional contact information
Jason Yang: California Institute of Technology
Ravi G. Lal: California Institute of Technology
James C. Bowden: California Institute of Technology
Raul Astudillo: California Institute of Technology
Mikhail A. Hameedi: California Institute of Technology
Sukhvinder Kaur: Elegen Corp
Matthew Hill: Elegen Corp
Yisong Yue: California Institute of Technology
Frances H. Arnold: California Institute of Technology

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Directed evolution (DE) is a powerful tool to optimize protein fitness for a specific application. However, DE can be inefficient when mutations exhibit non-additive, or epistatic, behavior. Here, we present Active Learning-assisted Directed Evolution (ALDE), an iterative machine learning-assisted DE workflow that leverages uncertainty quantification to explore the search space of proteins more efficiently than current DE methods. We apply ALDE to an engineering landscape that is challenging for DE: optimization of five epistatic residues in the active site of an enzyme. In three rounds of wet-lab experimentation, we improve the yield of a desired product of a non-native cyclopropanation reaction from 12% to 93%. We also perform computational simulations on existing protein sequence-fitness datasets to support our argument that ALDE can be more effective than DE. Overall, ALDE is a practical and broadly applicable strategy to unlock improved protein engineering outcomes.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-55987-8 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55987-8

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-55987-8

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().