Multiple protein structure alignment at scale with FoldMason
Open accessPublished version of a preprint
Abstract
Protein structure is conserved beyond sequence, making multiple structural alignment (MSTA) essential for analyzing distantly related proteins. Computational prediction methods have vastly extended our repository of available protein structures, requiring fast and accurate MSTA methods. We introduce FoldMason, a progressive MSTA method that leverages the pairwise structural aligners Foldseek and TM-align for the multiple alignment of hundreds of thousands of protein structures, matching or exceeding the alignment quality of state-of-the-art MSTA methods while being two orders of magnitude faster. Using Flaviviridae glycoproteins, we demonstrate that FoldMason’s MSTAs support phylogenetic analysis beyond the “twilight zone.” FoldMason computes confidence scores, offers interactive visualizations, and provides essential speed and accuracy for large-scale protein structure analysis in the era of accurate structure prediction. FoldMason is free, open-source software.
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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-citationModelFinder: fast model selection for accurate phylogenetic estimates
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Evolutionary-scale prediction of atomic level protein structure with a language model
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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
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Structural motif search across the protein universe with Folddisco
Kim, H., Kim, R. S., Mirdita, M., Yoon, J., & Steinegger, M. (2026) · Nature Biotechnology · doi:10.1038/s41587-026-03162-9 · Cited by 10 · see citing works
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- Authors
- Gilchrist, C. L. M., Mirdita, M., & Steinegger, M.
- Affiliations
- Seoul National University (KR)
- Corresponding author
- Steinegger, Martin
- Venue
- Science
- Published
- 2026-01-29
- Volume
- 391
- Issue
- 6784
- Pages
- 485-488
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W7126115639
- Cited by
- 117
- References
- 9
- Citations by year
- 2026: 56 · 2025: 57 · 2024: 4
- FWCI
- 115.74
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Seoul National University (Samsung DS research fund, Creative Pioneering Researchers Program, AI-Bio Research Grant)
- National Research Foundation of Korea (2020M3-A9G7-103933, RS-2021-NR061659, RS-2021-NR056571, RS-2024-00396026, RS-2023-00250470)
- National Research Foundation of Korea (NRF) grant funded by the Korea government (RS-2024-00440614)
- KBSI internal research programs (C539200)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- progressive alignment, Foldseek, TM-align, structural alignment, phylogenetic analysis, structural conservation, confidence scores, interactive visualization, open source software
- MeSH terms
- Glycoproteins, Phylogeny, Protein Conformation, Proteins, Software, Viral Envelope Proteins, Sequence Alignment, Flaviviridae, Computational Biology, Structural Homology, Protein
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