Bilingual language model for protein sequence and structure
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Abstract
Adapting language models to protein sequences spawned the development of powerful protein language models (pLMs). Concurrently, AlphaFold2 broke through in protein structure prediction. Now we can systematically and comprehensively explore the dual nature of proteins that act and exist as three-dimensional (3D) machines and evolve as linear strings of one-dimensional (1D) sequences. Here, we leverage pLMs to simultaneously model both modalities in a single model. We encode protein structures as token sequences using the 3Di-alphabet introduced by the 3D-alignment method Foldseek. For training, we built a non-redundant dataset from AlphaFoldDB and fine-tuned an existing pLM (ProtT5) to translate between 3Di and amino acid sequences. As a proof-of-concept for our novel approach, dubbed Protein ‘structure-sequence’ T5 (ProstT5), we showed improved performance for subsequent, structure-related prediction tasks, leading to three orders of magnitude speedup for deriving 3Di. This will be crucial for future applications trying to search metagenomic sequence databases at the sensitivity of structure comparisons. Our work showcased the potential of pLMs to tap into the information-rich protein structure revolution fueled by AlphaFold2. ProstT5 paves the way to develop new tools integrating the vast resource of 3D predictions and opens new research avenues in the post-AlphaFold2 era.
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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Self-citationNeedleman, S. B., & Wunsch, C. D. (1970) · Journal of Molecular Biology · doi:10.1016/0022-2836(70)90057-4 · Cited by 11,288 · see citing works
Exploring the Limits of Transfer Learning with a Unified Text-to-Text Transformer
Raffel, C., Shazeer, N., Roberts, A., Lee, K., Narang, S., Matena, M., Zhou, Y., Li, W., & Liu, P. J. (2019) · arXiv · doi:10.48550/arxiv.1910.10683 · Cited by 10,929 · see citing works
ColabFold - Making protein folding accessible to all
Mirdita, M., Schütze, K., Moriwaki, Y., Heo, L., Ovchinnikov, S., & Steinegger, M. (2021) · doi:10.1101/2021.08.15.456425 · Cited by 9,391 · see citing works
Self-citationEvolutionary-scale prediction of atomic level protein structure with a language model
Lin, Z., Akin, H., Rao, R., Hie, B., Zhu, Z., Lu, W., Smetanin, N., Verkuil, R., Kabeli, O., Shmueli, Y., et al. (2022) · doi:10.1101/2022.07.20.500902 · Cited by 5,523 · see citing works
Training language models to follow instructions with human feedback
Ouyang, L., Wu, J., Jiang, X., Almeida, D., Wainwright, C. L., Mishkin, P., Zhang, C., Agarwal, S., Slama, K., Ray, A., et al. (2022) · arXiv · doi:10.48550/arxiv.2203.02155 · Cited by 4,208 · see citing works
Catastrophic Interference in Connectionist Networks: The Sequential Learning Problem
McCloskey, M., & Cohen, N. J. (1989) · Psychology of Learning and Motivation · doi:10.1016/s0079-7421(08)60536-8 · Cited by 3,770 · see citing works
Rives, A., Meier, J., Sercu, T., Goyal, S., Lin, Z., Liu, J., Guo, D., Ott, M., Zitnick, C. L., Ma, J., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2016239118 · Cited by 3,286 · see citing works
Rives, A., Meier, J., Sercu, T., Goyal, S., Lin, Z., Liu, J., Guo, D., Ott, M., Zitnick, C. L., Ma, J., et al. (2019) · doi:10.1101/622803 · Cited by 3,280 · cited 1× · see citing works
“…: embedding-based annotation transfer using the shortest Euclidean distance measured in embedding space of unsupervised pLMs ESM-1b [5], ProtT5 and ProstT5 with different inputs (AA=amino acid sequence input, p3Di=3Di predicted by ProstT5, 3Di=3Di from experimental structures,…”
Fast and accurate protein structure search with Foldseek
van Kempen, M., Kim, S. S., Tumescheit, C., Mirdita, M., Lee, J., Gilchrist, C. L. M., Söding, J., & Steinegger, M. (2022) · doi:10.1101/2022.02.07.479398 · Cited by 2,598 · see citing works
Self-citationFast and accurate protein structure search with Foldseek
van Kempen, M., Kim, S. S., Tumescheit, C., Mirdita, M., Lee, J., Gilchrist, C. L. M., Söding, J., & Steinegger, M. (2024) · Nature Biotechnology · doi:10.1038/s41587-023-01773-0 · Cited by 2,596 · see citing works
Self-citationProtTrans: Toward Understanding the Language of Life Through Self-Supervised Learning
Elnaggar, A., Heinzinger, M., Dallago, C., Rehawi, G., Wang, Y., Jones, L., Gibbs, T., Feher, T., Angerer, C., Steinegger, M., et al. (2022) · IEEE Transactions on Pattern Analysis and Machine Intelligence · doi:10.1109/tpami.2021.3095381 · Cited by 2,329 · see citing works
Robust deep learning based protein sequence design using ProteinMPNN
Dauparas, J., Anishchenko, I., Bennett, N., Bai, H., Ragotte, R. J., Milles, L. F., Wicky, B. I. M., Courbet, A., de Haas, R. J., Bethel, N., et al. (2022) · doi:10.1101/2022.06.03.494563 · Cited by 2,107 · see citing works
Robust deep learning–based protein sequence design using ProteinMPNN
Dauparas, J., Anishchenko, I., Bennett, N., Bai, H., Ragotte, R. J., Milles, L. F., Wicky, B. I. M., Courbet, A., de Haas, R. J., Bethel, N., et al. (2022) · Science · doi:10.1126/science.add2187 · Cited by 2,070 · see citing works
Varadi, M., Bertoni, D., Magana, P., Paramval, U., Pidruchna, I., Radhakrishnan, M., Tsenkov, M., Nair, S., Mirdita, M., Yeo, J., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkad1011 · Cited by 2,052 · cited 2× · see citing works
“This revolution opens up exciting possibilities to explore the dual nature of proteins - from their one-dimensional (1D) amino acid sequences to their unique three-dimensional (3D) structures.”
BackgroundSelf-citationUniRef: comprehensive and non-redundant UniProt reference clusters
Suzek, B. E., Huang, H., McGarvey, P., Mazumder, R., & Wu, C. H. (2007) · Bioinformatics · doi:10.1093/bioinformatics/btm098 · Cited by 1,613 · see citing works
The Curious Case of Neural Text Degeneration
Holtzman, A., Buys, J., Du, L., Forbes, M., & Choi, Y. (2019) · arXiv · doi:10.48550/arxiv.1904.09751 · Cited by 1,304 · see citing works
Hierarchical Neural Story Generation
Fan, A., Lewis, M., & Dauphin, Y. (2018) · arXiv · doi:10.48550/arxiv.1805.04833 · Cited by 1,242 · see citing works
Tree of Thoughts: Deliberate Problem Solving with Large Language Models
Yao, S., Yu, D., Zhao, J., Shafran, I., Griffiths, T. L., Cao, Y., & Narasimhan, K. (2023) · arXiv · doi:10.48550/arxiv.2305.10601 · Cited by 1,158 · see citing works
A structural biology community assessment of AlphaFold2 applications
Akdel, M., Pires, D. E. V., Pardo, E. P., Jänes, J., Zalevsky, A. O., Mészáros, B., Bryant, P., Good, L. L., Laskowski, R. A., Pozzati, G., et al. (2022) · Nature Structural & Molecular Biology · doi:10.1038/s41594-022-00849-w · Cited by 675 · see citing works
Nucleotide Transformer: building and evaluating robust foundation models for human genomics
Dalla-Torre, H., Gonzalez, L., Mendoza-Revilla, J., Lopez Carranza, N., Grzywaczewski, A. H., Oteri, F., Dallago, C., Trop, E., de Almeida, B. P., Sirelkhatim, H., et al. (2025) · Nature Methods · doi:10.1038/s41592-024-02523-z · Cited by 656 · see citing works
Modeling the language of life – Deep Learning Protein Sequences
Heinzinger, M., Elnaggar, A., Wang, Y., Dallago, C., Nechaev, D., Matthes, F., & Rost, B. (2019) · doi:10.1101/614313 · Cited by 606 · see citing works
Self-citationProtein-level assembly increases protein sequence recovery from metagenomic samples manyfold
Steinegger, M., Mirdita, M., & Söding, J. (2019) · Nature Methods · doi:10.1038/s41592-019-0437-4 · Cited by 445 · see citing works
Self-citationLanguage models generalize beyond natural proteins
Verkuil, R., Kabeli, O., Du, Y., Wicky, B. I. M., Milles, L. F., Dauparas, J., Baker, D., Ovchinnikov, S., Sercu, T., & Rives, A. (2022) · doi:10.1101/2022.12.21.521521 · Cited by 181 · cited 1× · see citing works
“The same knowledge extracted by the pLM, can also be queried for protein design [22]–[24], dynamic optimization [25]–[27] or the inference of drug-target interactions [28].”
Protein language model embeddings for fast, accurate, alignment-free protein structure prediction
Weissenow, K., Heinzinger, M., & Rost, B. (2021) · doi:10.1101/2021.07.31.454572 · Cited by 139 · see citing works
Self-citationAlphaFold2 reveals commonalities and novelties in protein structure space for 21 model organisms
Bordin, N., Sillitoe, I., Nallapareddy, V., Rauer, C., Lam, S. D., Waman, V. P., Sen, N., Heinzinger, M., Littmann, M., Kim, S., et al. (2023) · Communications Biology · doi:10.1038/s42003-023-04488-9 · Cited by 103 · see citing works
Self-citation
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<scp>ESM</scp> ‐scan—A tool to guide amino acid substitutions
Totaro, M. G., Vide, U., Zausinger, R., Winkler, A., & Oberdorfer, G. (2024) · Protein Science · doi:10.1002/pro.5221 · Cited by 19 · see citing works
Ghaly, T. M., Rajabal, V., Russell, D., Colombi, E., & Tetu, S. G. (2025) · doi:10.1101/2025.04.02.646905 · Cited by 5 · see citing works
Multimodal graph, surface, and language-based model for protein protein interaction prediction
Arteaga, D., Chervov, N., & Poptsova, M. (2026) · Scientific Reports · doi:10.1038/s41598-025-34758-x · Cited by 3 · see citing works
- Authors
- Heinzinger, M., Weissenow, K., Sanchez, J. G., Henkel, A., Mirdita, M., Steinegger, M., & Rost, B.
- Affiliations
- Technical University of Munich (DE)
- School of Computation, Information, and Technology (CIT), Department of Informatics, Bioinformatics & Computational Biology, TUM (Technical University of Munich) , 85748 Garching/Munich,
- Seoul National University (KR)
- Corresponding author
- Heinzinger, Michael
- Venue
- NAR Genomics and Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2024-09-28
- Volume
- 6
- Issue
- 4
- Pages
- lqae150-lqae150
- ISSN
- 2631-9268 (ISSN-L)
- PMC
- PMC11616678
- OpenAlex
- W4404447386
- Cited by
- 311
- References
- 26
- Citations by year
- 2026: 111 · 2025: 144 · 2024: 48 · 2023: 7 · 2012: 1
- FWCI
- 41.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- NAR Genomics and Bioinformatics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Bavarian Ministry of Education
- TUM
- German Ministry for Research and Education
- Deutsche Forschungsgemeinschaft (DFG-GZ: RO1320/4-1)
- National Research Foundation of Korea (2020M3-A9G7-103933, 2021-R1C1-C102065, 2021-M3A9-I4021220, RS-2023-00250470)
- Creative-Pioneering Researchers Program through Seoul National University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- protein language models, protein structure prediction, protein sequence prediction, Foldseek, AlphaFold2, ProtT5
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