biostudies-literatureKim WNational Research Foundation of Korea (NRF)EC | Horizon 2020 Framework ProgrammeNational Research Foundation of KoreaSeoul National UniversityEC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)469-472https://www.ebi.ac.uk/biostudies/studies/S-EPMC11903335biostudies-literatureUnknown22(3)Advances in computational structure prediction will vastly augment the hundreds of thousands of currently available protein complex structures. Translating these into discoveries requires aligning them, which is computationally prohibitive. Foldseek-Multimer computes complex alignments from compatible chain-to-chain alignments, identified by efficiently clustering their superposition vectors. Foldseek-Multimer is 3-4 orders of magnitudes faster than the gold standard, while producing comparable alignments; this allows it to compare billions of complex pairs in 11 h. Foldseek-Multimer is open-source software available at GitHub via https://github.com/steineggerlab/foldseek/ , https://search.foldseek.com/search/ and the BFMD database.Nature methodsRapid and sensitive protein complex alignment with Foldseek-Multimer.PMC119033352021-M3A9-I40212202021-R1C1-C102065Creative-Pioneering Researchers Program819318RS-2024-00396026RS-2023-00250470AI-Bio Research GrantSoding JLevy Karin EKim WSchweke HLevy EDMirdita MGilchrist CLMSteinegger MfalseRapid and sensitive protein complex alignment with Foldseek-Multimer.Advances in computational structure prediction will vastly augment the hundreds of thousands of currently available protein complex structures. Translating these into discoveries requires aligning them, which is computationally prohibitive. Foldseek-Multimer computes complex alignments from compatible chain-to-chain alignments, identified by efficiently clustering their superposition vectors. Foldseek-Multimer is 3-4 orders of magnitudes faster than the gold standard, while producing comparable alignments; this allows it to compare billions of complex pairs in 11 h. Foldseek-Multimer is open-source software available at GitHub via https://github.com/steineggerlab/foldseek/ , https://search.foldseek.com/search/ and the BFMD database.2025-01-01T00:00:00Z2025 Mar2026-06-02T21:05:19.114Z2025-04-03T23:56:49.38ZS-EPMC119033353991025110.1038/s41592-025-02593-7