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Clustering predicted structures at the scale of the known protein universe

Cited 16 time in Web of Science Cited 20 time in Scopus

Barrio-Hernandez, Inigo; Yeo, Jingi; Jänes, Jürgen; Mirdita, Milot; Gilchrist, Cameron L. M.; Wein, Tanita; Varadi, Mihaly; Velankar, Sameer; Beltrao, Pedro; Steinegger, Martin

Issue Date
Nature Research
Nature, Vol.622 No.7983, pp.637-645
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 accuracy1, and over 214 million predicted structures are available in the AlphaFold database2. 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.
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Related Researcher

  • College of Natural Sciences
  • School of Biological Sciences
Research Area Development of algorithms to search, cluster and assemble sequence data, Metagenomic analysis, Pathogen detection in sequencing data


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