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A generalized platform for artificial intelligence-powered autonomous enzyme engineering

Author

Listed:
  • Nilmani Singh

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Stephan Lane

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Tianhao Yu

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Jingxia Lu

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Adrianna Ramos

    (University of Illinois Urbana-Champaign)

  • Haiyang Cui

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

  • Huimin Zhao

    (University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign
    University of Illinois Urbana-Champaign)

Abstract

Proteins are the molecular machines of life with numerous applications in energy, health, and sustainability. However, engineering proteins with desired functions for practical applications remains slow, expensive, and specialist-dependent. Here we report a generally applicable platform for autonomous enzyme engineering that integrates machine learning and large language models with biofoundry automation to eliminate the need for human intervention, judgement, and domain expertise. Requiring only an input protein sequence and a quantifiable way to measure fitness, this automated platform can be applied to engineer a wide array of proteins. As a proof of concept, we engineer Arabidopsis thaliana halide methyltransferase (AtHMT) for a 90-fold improvement in substrate preference and 16-fold improvement in ethyltransferase activity, along with developing a Yersinia mollaretii phytase (YmPhytase) variant with 26-fold improvement in activity at neutral pH. This is accomplished in four rounds over 4 weeks, while requiring construction and characterization of fewer than 500 variants for each enzyme. This platform for autonomous experimentation paves the way for rapid advancements across diverse industries, from medicine and biotechnology to renewable energy and sustainable chemistry.

Suggested Citation

  • Nilmani Singh & Stephan Lane & Tianhao Yu & Jingxia Lu & Adrianna Ramos & Haiyang Cui & Huimin Zhao, 2025. "A generalized platform for artificial intelligence-powered autonomous enzyme engineering," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61209-y
    DOI: 10.1038/s41467-025-61209-y
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    References listed on IDEAS

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