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Unified rational protein engineering with sequence-based deep representation learning


Rational protein engineering requires a holistic understanding of protein function. Here, we apply deep learning to unlabeled amino-acid sequences to distill the fundamental features of a protein into a statistical representation that is semantically rich and structurally, evolutionarily and biophysically grounded. We show that the simplest models built on top of this unified representation (UniRep) are broadly applicable and generalize to unseen regions of sequence space. Our data-driven approach predicts the stability of natural and de novo designed proteins, and the quantitative function of molecularly diverse mutants, competitively with the state-of-the-art methods. UniRep further enables two orders of magnitude efficiency improvement in a protein engineering task. UniRep is a versatile summary of fundamental protein features that can be applied across protein engineering informatics.

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Fig. 1: Workflow to learn and apply deep protein representations.
Fig. 2: UniRep encodes amino-acid physicochemistry, organism level information, secondary structure, evolutionary and functional information, and higher-order structural features.
Fig. 3: UniRep predicts structural and functional properties of proteins.
Fig. 4: UniRep, fine-tuned to a local evolutionary context, facilitates protein engineering by enabling generalization to distant peaks in the sequence landscape.

Data availability

All data are available in the main text or the supplementary materials.

Code availability

Code for UniRep model training and inference with trained weights along with links to all necessary data is available in a public repository at Code to reproduce all analysis and regenerate figures with links to preprocessed benchmark datasets is available online


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We thank J. Aach, A. Taylor-Weiner, D. Goodman, P. Ogden, G. Kuznetsov, S. Sinai, A. Tucker, M. Turpin, J. Swett, N. Thomas, R. Sha, C. Bakerlee and K. Fish for valuable feedback and discussion. S.B. was supported by an NIH Training Grant (no. T32HG002295) to the Harvard Bioinformatics and Integrative Genomics program as well as an NSF GRFP Fellowship. M.A. was supported through NIGMS Grant no. P50GM107618 and NIH grant no. U54-CA225088. E.C.A. and G.K. were supported by the Center for Effective Altruism. E.C.A. was partially supported by the Wyss Institute for Biologically Inspired Engineering. Computational resources were, in part, generously provided by the AWS Cloud Credits for the Research program.

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Authors and Affiliations



E.C.A. and G.K. conceived the study. E.C.A., G.K. and S.B. conceived the experiments, managed data and performed the analysis. M.A. performed large-scale RGN inference and managed data and software for parts of the analysis. G.M.C. supervised the project. E.C.A., G.K. and S.B. wrote the manuscript with help from all authors.

Corresponding author

Correspondence to George M. Church.

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Competing interests

E.C.A., G.K. and S.B. are in the process of pursuing a patent on this technology. S.B. is a former consultant for Flagship Pioneering company VL57 (now VL56). A full list of G.M.C.’s tech transfer, advisory roles and funding sources can be found on the laboratory’s website:

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Peer review information Nicole Rusk was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary Information

Supplementary Figs. 1–15 and Tables 1–9.

Reporting Summary

Supplementary Data Set 1

All test set results in .xlsx format

Supplementary Data Set 2

All validation set results in .xlsx format

Supplementary Data Set 3

All test set results graphically presented in .pdf format

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Alley, E.C., Khimulya, G., Biswas, S. et al. Unified rational protein engineering with sequence-based deep representation learning. Nat Methods 16, 1315–1322 (2019).

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