| name | foldseek |
| description | Foldseek — ultrafast protein structure search and clustering via the 3Di structural alphabet (Steinegger / Söding labs). Use when: (1) Searching MAG or predicted structures against AFDB/PDB/ESM Atlas, (2) Foldseek-Multimer complex search for distant systems (e.g. CRISPR–Cas), (3) Structure clustering at AFDB scale, (4) Sequence→structure search with ProstT5. Upstream: https://github.com/steineggerlab/foldseek. Web: https://search.foldseek.com. Route via homology-search / metagenomics-llm; pairs with mmseqs2 (sequence) and folddisco (motifs).
|
| license | MIT |
| category | analysis-tools |
| tags | ["Foldseek","3Di","structure-search","AFDB","multimer","ProstT5","homology"] |
| upstream | https://github.com/steineggerlab/foldseek |
| stage | function |
Foldseek
Upstream: steineggerlab/foldseek ·
Web: https://search.foldseek.com
Citation
van Kempen, M. et al. Fast and accurate protein structure search with Foldseek.
Nat. Biotechnol. 42, 243–246 (2024). https://doi.org/10.1038/s41587-023-01773-0
Kim, W. et al. Rapid and sensitive protein complex alignment with
Foldseek-Multimer. Nat. Methods 22, 469–472 (2025).
https://doi.org/10.1038/s41592-025-02593-7
Barrio-Hernandez, I. et al. Clustering predicted structures at the scale of
the known protein universe. Nature 622, 637–645 (2023).
https://doi.org/10.1038/s41586-023-06510-w
See also docs/references.md.
Analytical thinking
Sequence search (mmseqs2 / diamond) fails for many remote homologs. Foldseek
turns tertiary geometry into a 3Di letter sequence and reuses MMseqs2-style
prefilters — roughly 10⁴–10⁵× faster than TM-align/Dali/CE with comparable
sensitivity. Metagenomics use cases: AFDB/ESMAtlas annotation of dark MAG
proteins, structural NR clustering, and complex-level mining
(easy-multimersearch).
Martin Steinegger “AI and evolution” stack (conservation level → tool):
| Level | Prefer |
|---|
| Sequence / single-chain structure | mmseqs2 · foldseek |
| Multimer / interface | Foldseek-Multimer (easy-multimersearch) |
| Local structural motif | folddisco |
| Conserved gene neighborhoods | spacedust (uses Foldseek) |
| vs | Prefer Foldseek when |
|---|
mmseqs2 / diamond | Structures or ProstT5 path available; twilight-zone homology |
plmsearch / deepblast | Real/predicted structures exist (or AFDB targets) |
folddisco | Need whole-chain / complex fold match, not a short motif |
| TM-align / US-align | Database-scale search (not gold-standard pairwise polish) |
Hard rules:
- Structural hits ≠ experimental function — pin AFDB/PDB release + Foldseek version
- Low-confidence AF models (pLDDT) inflate false positives — filter inputs
- Multimer claims need chain pairing / complex TM reporting, not monomer E-values alone
- Do not merge Foldseek tables with BLAST/MMseqs unlabeled
How to run
foldseek databases Alphafold/Proteome afdb tmp
foldseek databases PDB pdb tmp
foldseek easy-search query.pdb afdb aln.m8 tmp
foldseek databases ProstT5 weights tmp
foldseek easy-search QUERY.faa pdb res.m8 tmp --prostt5-model weights
foldseek easy-cluster structures/ clu tmp -c 0.9
foldseek easy-multimersearch query_complex.pdb.gz pdb mm_result tmp
Webserver for interactive queries: https://search.foldseek.com
Key parameters
| Setting | Notes |
|---|
| Input | PDB/mmCIF structures, or FASTA + --prostt5-model |
| Target DBs | AFDB proteomes, PDB100, ESMAtlas clusters — pin release |
--alignment-type | 3Di/AA vs TM-align-style rescoring when needed |
--cluster-search | Clustered DBs (AFDB50): reps-only vs expand members |
--gpu | Optional GPU prefilter (Ampere+ preferred) |
| Multimer report | Use _report for chain pairing, TM, transforms |
Decision tree
Homology / structure need?
├─ Close sequence homologs → mmseqs2 / diamond
├─ Dark proteins, have/ predict structures → foldseek easy-search
├─ Sequence-only, no GPU structures → foldseek+ProstT5 or plmsearch / deepblast
├─ Multi-chain complexes / interfaces → foldseek easy-multimersearch
├─ Short active-site / motif geometry → folddisco
├─ Conserved neighborhoods → spacedust
└─ Structure NR catalogue → foldseek easy-cluster
Related skills
homology-search · protein-language-model · prostt5 · esm ·
foldcomp · folddisco · foldmason · unicore · mmseqs2 · hh-suite ·
petasearch · spacedust · plmsearch · deepblast · eggnog-mapper ·
microbial-mining · tool-selection
