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Large language models generate functional protein sequences across diverse families

Nature Biotechnology (2023)Cite this article

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Abstract

Deep-learning language models have shown promise in various biotechnological applications, including protein design and engineering. Here we describe ProGen, a language model that can generate protein sequences with a predictable function across large protein families, akin to generating grammatically and semantically correct natural language sentences on diverse topics. The model was trained on 280 million protein sequences from >19,000 families and is augmented with control tags specifying protein properties. ProGen can be further fine-tuned to curated sequences and tags to improve controllable generation performance of proteins from families with sufficient homologous samples. Artificial proteins fine-tuned to five distinct lysozyme families showed similar catalytic efficiencies as natural lysozymes, with sequence identity to natural proteins as low as 31.4%. ProGen is readily adapted to diverse protein families, as we demonstrate with chorismate mutase and malate dehydrogenase.

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Fig. 1: Artificial protein generation with conditional language modeling.
Fig. 2: Generated artificial antibacterial proteins are diverse and express well in our experimental system.
Fig. 3: Artificial protein sequences are functional while reaching as low as 31% identity to any known protein, exhibit comparable catalytic efficiencies to a highly-evolved natural protein, and demonstrate similar structures to known natural folds.
Fig. 4: Applicability of conditional language modeling to other protein systems.

Data availability

All sequence databases used in this study are publicly available and include UniprotKB, UniParc, NCBI Taxonomy, Pfam, Uniref30, NCBI nr database and Interpro. Please refer to Supplementary Table 1 for more details. Sequences and activity data for natural and artificial lysozymes tested are in the Supplementary Material. Evaluation data for the CM experiments can be found in Russ et al.6. Evaluation data for the MDH experiments can be found in Repecka et al.52. The crystal structure datasets generated during the current study are available under PDB accession 7RGR. Source data are provided with this paper.

Code availability

Our code and checkpoints are publicly available on Zenodo and can be reproduced using the details provided in the Methods section on data preparation, model architecture and training protocol. Major components of our model architecture and training protocol can be reproduced using CTRL (https://github.com/salesforce/ctrl). The most updated and supported codebase can be found at https://github.com/salesforce/progen.

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Acknowledgements

We thank B. McCann, C. Gee, E. Procko, K. Trego, L. Varshney, N. Shirish Keskar and S. Savarese for their feedback at various stages of this project. We thank A. Cook, D. Lo and V. Nemali for operational support. Thanks also to the Salesforce Research Computing Infrastructure team and the Google Cloud TPU team for their help with computing resources, in addition to Twist Bioscience for DNA synthesis support. Beamline 8.3.1 at the Advanced Light Source is operated by the University of California Office of the President, Multicampus Research Programs and Initiatives grant MR-15-328599, the National Institutes of Health (R01 GM124149 and P30 GM124169), Plexxikon Inc. and the Integrated Diffraction Analysis Technologies program of the US Department of Energy Office of Biological and Environmental Research. The Advanced Light Source (Berkeley, CA) is a national user facility operated by Lawrence Berkeley National Laboratory on behalf of the US Department of Energy under contract number DE-AC02-05CH11231, Office of Basic Energy Sciences. Icons in one figure were created using BioRender (https://biorender.com). E.R.G. is supported by NIH F32-GM144982-01. J.S.F. was supported by NIH GM123159, NIH GM145238 and a Sanghvi-Agarwal Innovation Award.

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Author notes

  1. These authors contributed equally: Ben Krause and Eric R. Greene.

Authors and Affiliations

  1. Salesforce Research, Palo Alto, CA, USA

    Ali Madani, Ben Krause, Caiming Xiong, Richard Socher & Nikhil Naik

  2. Profluent Bio, San Francisco, CA, USA

    Ali Madani

  3. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA

    Eric R. Greene, Jose Luis Olmos Jr. & James S. Fraser

  4. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA

    Subu Subramanian

  5. Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA

    Subu Subramanian

  6. Tierra Biosciences, San Leandro, CA, USA

    Benjamin P. Mohr & Zachary Z. Sun

  7. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA

    James M. Holton

  8. Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, Menlo Park, CA, USA

    James M. Holton

  9. Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA

    James M. Holton

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Contributions

A.M. conceived and designed the study in collaboration with S.S. A.M. and B.K. designed and performed machine learning modeling, generation and scoring. B.P.M. performed the cell-free expression and activity assay and was supervised by Z.Z.S. E.R.G. performed the cell-based expression and kinetics assay and was supervised by J.S.F. J.M.H., J.L.O., J.S.F. performed the structure determination. A.M., S.S., B.K. and N.N. performed computational analysis, and were advised by C.X. R.S. provided advice on machine learning and computational methods. A.M., J.S.F. and N.N. wrote the manuscript with feedback and contributions from all authors, in particular from E.G. and B.K. N.N. supervised and managed the project.

Corresponding authors

Correspondence to Ali Madani or Nikhil Naik.

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A.M. is a co-founder of Profluent Bio. All other authors declare no competing interests.

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Supplementary Information

Supplementary Tables 1–7, Supplementary Figures 1–12 and Supplementary References.

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Source data

Source Data Fig. 1

Experimental data for protein sequences and activity.

Source Data Fig. 2

Structure report for artificial lysozyme deposited as 7RGR.

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Madani, A., Krause, B., Greene, E.R. et al. Large language models generate functional protein sequences across diverse families. Nat Biotechnol (2023). https://doi.org/10.1038/s41587-022-01618-2

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