Clustering predicted structures at the scale of the known protein universe

By Inigo Barrio Hernandez, Jingi Yeo, Jürgen Jänes, Tanita Wein, Mihaly Varadi, S. Velankar, Pedro Beltrão, Martin Steinegger. bioRxiv, 2023

308 citations recorded by the source corpus.

The novel Foldseek clustering algorithm defines 2.30 million clusters of AlphaFold structures, identifying remote structural similarity of human immune-related proteins in prokaryotic species. Proteins are key to all cellular processes and their structure is important in understanding their function and evolution. Sequence-based predictions of protein structures have increased in accuracy^ 1 , and over 214 million predicted structures are available in the AlphaFold database^ 2 . However, studying protein structures at this scale requires highly efficient methods. Here, we developed a structural-alignment-based clustering algorithm—Foldseek cluster—that can cluster hundreds of millions of structures. Using this method, we have clustered all of the structures in the AlphaFold database, identifying 2.30 million non-singleton structural clusters, of which 31% lack annotations representing probable previously undescribed structures. Clusters without annotation tend to have few representatives covering only 4% of all proteins in the AlphaFold database. Evolutionary analysis suggests that most clusters are ancient in origin but 4% seem to be species specific, representing lower-quality predictions or examples of de novo gene birth. We also show how structural comparisons can be used to predict domain families and their relationships, identifying examples of remote structural similarity. On the basis of these analyses, we identify several examples of human immune-related proteins with putative remote homology in prokaryotic species, illustrating the value of this resource for studying protein function and evolution across the tree of life.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0320061f488adb79d82b6fa9d7e6e4618c9cf48b

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In Molecular Biology

Citations in the corpus

AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences (2023, background): “Tackling this challenge, Steinegger et al. recently unveiled the Foldseek Cluster, a state-of-the-art structural-alignment-based clustering algorithm designed for vast datasets ( 22 ).”
Gaia: An AI-enabled genomic context–aware platform for protein sequence annotation (2025, unknown): “We fine-tune gLM2 contrastively on 2.3 million structural clusters of the AlphaFoldDB (see Materials and Methods) ( 22 ), yielding a structure-aligned and context-aware retrieval model (gLM2_embed) (Fig.”