Foldseek-Interface reveals a protein interface universe far from complete
- 1Institute of Molecular Biology
Abstract
Protein-protein interactions mediate a vast range of cellular functions, requiring diverse modes of binding. While recent years have seen major efforts to chart and classify the protein structure universe, we lack comparable methods to assess and cluster that diversity in interface structure at interactome scale. Here, we present Foldseek-Interface, a method that converts 3D interface structures into searchable sequences to enable fast alignment and clustering of protein interaction interfaces. It matches the accuracy of state-of-the-art tools while running up to 230 times faster. Applying it to all biological assemblies in the PDB, we cluster 3.1 million dimers into 77{,}167 interface clusters and use this resource to characterise interface diversity, evolution, and pathogen mimicry. Application of Foldseek-Interface to resources of predicted protein complex structures rapidly revealed putatively novel interface types worth further experimental interrogation. Foldseek-Interface and the interface cluster resource are freely available as webservers for search https://search.foldseek.com/interface and exploration https://interface.foldseek.com.
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BibTeX
@misc{strom2026foldseekinterface,
title = {{Foldseek-Interface reveals a protein interface universe far from complete}},
author = {J. M. Strom and S. Cha and R. S. Kim and H. Sajal and C. L. Gilchrist and M. Steinegger and K. Luck},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.24.746585},
url = {https://www.biorxiv.org/content/10.64898/2026.08.24.746585v2},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Foldseek-Interface reveals a protein interface universe far from complete
AU - J. M. Strom
AU - S. Cha
AU - R. S. Kim
AU - H. Sajal
AU - C. L. Gilchrist
AU - M. Steinegger
AU - K. Luck
PY - 2026
DA - 2026/08/24
PB - bioRxiv
DO - 10.64898/2026.08.24.746585
UR - https://www.biorxiv.org/content/10.64898/2026.08.24.746585v2
AB - Protein-protein interactions mediate a vast range of cellular functions, requiring diverse modes of binding. While recent years have seen major efforts to chart and classify the protein structure universe, we lack comparable methods to assess and cluster that diversity in interface structure at interactome scale. Here, we present Foldseek-Interface, a method that converts 3D interface structures into searchable sequences to enable fast alignment and clustering of protein interaction interfaces. It matches the accuracy of state-of-the-art tools while running up to 230 times faster. Applying it to all biological assemblies in the PDB, we cluster 3.1 million dimers into 77{,}167 interface clusters and use this resource to characterise interface diversity, evolution, and pathogen mimicry. Application of Foldseek-Interface to resources of predicted protein complex structures rapidly revealed putatively novel interface types worth further experimental interrogation. Foldseek-Interface and the interface cluster resource are freely available as webservers for search https://search.foldseek.com/interface and exploration https://interface.foldseek.com.
ER -