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Single-sequence protein structure prediction using supervised transformer protein language models

Nature Computational Science volume 2, pages 804–814 (2022)Cite this article

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A preprint version of the article is available at bioRxiv.

Abstract

Significant progress has been made in protein structure prediction in recent years. However, it remains challenging for AlphaFold2 and other deep learning-based methods to predict protein structure with single-sequence input. Here we introduce trRosettaX-Single, an automated algorithm for single-sequence protein structure prediction. It incorporates the sequence embedding from a supervised transformer protein language model into a multi-scale network enhanced by knowledge distillation to predict inter-residue two-dimensional geometry, which is then used to reconstruct three-dimensional structures via energy minimization. Benchmark tests show that trRosettaX-Single outperforms AlphaFold2 and RoseTTAFold on orphan proteins and works well on human-designed proteins (with an average template modeling score (TM-score) of 0.79). An experimental test shows that the full trRosettaX-Single pipeline is two times faster than AlphaFold2, using much fewer computing resources (<10%). On 2,000 designed proteins from network hallucination, trRosettaX-Single generates structure models with high confidence. As a demonstration, trRosettaX-Single is applied to missense mutation analysis. These data suggest that trRosettaX-Single may find potential applications in protein design and related studies.

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Fig. 1: The architecture and performance of trRosettaX-Single.
Fig. 2: Comparison between trRosettaX-Single, AlphaFold2 and RoseTTAFold on two example proteins.
Fig. 3: Comparison between trRosettaX-Single and SPOT-Contact-LM.
Fig. 4: Application to hallucinated proteins.
Fig. 5: Mutation analysis on human-designed proteins and three deep mutational scanning datasets.
Fig. 6: Ablation study and estimation of model accuracy.

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Data availability

The data supporting the findings and conclusions of this study are available in this paper and its Supplementary Information. All of the training and test data used in this work are available at Zenodo39 and our website (https://yanglab.nankai.edu.cn/trRosetta/benchmark_single/). The experimental 3D structures can be downloaded from PDB (https://www.rcsb.org/). The Orphan25 dataset includes 25 natural proteins that were published after May 2020 and have no sequence homologs in UniRef50_2018_03 with MMseqs2 search at an e-value cut-off of 0.05. The Design55 dataset includes 55 human-designed proteins that have no sequence homologs in UniRef50_2018_03. The designed proteins are of size between 50 and 300 amino acids. We removed proteins that are in simple topologies (for example, a single alpha helix) or have hits in the training sets at an e-value cut-off of 0.1 by PSI-BLAST. Source data for Figs. 1b,c and 2–6 are provided with this paper.

Code availability

The source code is available at Zenodo39 and our website (https://yanglab.nankai.edu.cn/trRosetta/benchmark_single/).

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Acknowledgements

This work is supported in part by the National Natural Science Foundation of China (NSFC T2225007, T2222012, 11871290 and 61873185), and the Foundation for Innovative Research Groups of State Key Laboratory of Microbial Technology (WZCX2021-03).

Author information

Authors and Affiliations

  1. School of Mathematical Sciences, Nankai University, Tianjin, China

    Wenkai Wang

  2. Ministry of Education Frontiers Science Center for Nonlinear Expectations, Research Center for Mathematics and Interdisciplinary Sciences, Shandong University, Qingdao, China

    Zhenling Peng & Jianyi Yang

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Contributions

J.Y. designed the research. W.W. developed the pipeline and carried out the experiments. J.Y. and P.Z. supervised the research. All authors analyzed data, wrote and revised the manuscript.

Corresponding author

Correspondence to Jianyi Yang.

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The authors declare no competing interests.

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Peer review information

Nature Computational Science thanks Arne Elofsson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jie Pan, in collaboration with the Nature Computational Science team.

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Supplementary information

Supplementary Information

Supplementary Tables 1–6 and Figs. 1–11.

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Source data

Source Data Fig. 1

The distance precisions and TM scores in Fig. 1.

Source Data Fig. 2

The predicted distances and structures for 7JJV and 2LSE in Fig. 2.

Source Data Fig. 3

Contact precision data for trRosettaX-Single and SPOT-Contact-LM in Fig. 3.

Source Data Fig. 4

Estimated TM scores for 2,000 hallucinated proteins and PDB files for three examples in Fig. 4.

Source Data Fig. 5

Data for mutation effect analysis in Fig. 5.

Source Data Fig. 6

Data for ablation study and estimated TM score in Fig. 6.

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Cite this article

Wang, W., Peng, Z. & Yang, J. Single-sequence protein structure prediction using supervised transformer protein language models. Nat Comput Sci 2, 804–814 (2022). https://doi.org/10.1038/s43588-022-00373-3

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