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Protein engineering

Hallucinating functional protein sequences

Nature Biotechnology (2023)Cite this article

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Functional proteins with limited homology to natural proteins are designed using a large language model.

Directed evolution has proven remarkably successful at finding variants of known proteins with enhanced properties1. Yet designing proteins that are not homologous to those found in nature is extremely challenging. The strategy of walking uphill on a rugged protein fitness landscape can stall at local optima, making it hard to discover diverse functional variants. Techniques such as DNA shuffling recombine parental variants and allow larger moves in sequence space, but diverse variants are rarely generated because the synthesis process favors sequence-similar parents.

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Fig. 1: ProGen.

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Authors and Affiliations

  1. Google Research, Mountain View, CA, USA

    David Belanger & Lucy J. Colwell

  2. Department of Chemistry, Cambridge University, Cambridge, UK

    Lucy J. Colwell

Authors
  1. David Belanger
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  2. Lucy J. Colwell
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Correspondence to Lucy J. Colwell.

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Competing interests

D.B. and L.J.C. have performed research as part of their employment at Google LLC. Google is a technology company that sells machine learning services as part of its business.

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Belanger, D., Colwell, L.J. Hallucinating functional protein sequences. Nat Biotechnol (2023). https://doi.org/10.1038/s41587-022-01634-2

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  • DOI: https://doi.org/10.1038/s41587-022-01634-2

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