Proteins that are known only at a sequence level outnumber those with an experimental characterization by orders of magnitude. Classifying protein regions (domains) into homologous families can generate testable functional hypotheses for yet unannotated sequences. Existing domain family resources typically use at least some degree of manual curation: they grow slowly over time and leave a large fraction of the protein sequence space unclassified. We here describe automatic clustering by Density Peak Clustering of UniRef50 v. 2017_07, a protein sequence database including approximately 23M sequences. We performed a radical re-implementation of a pipeline we previously developed in order to allow handling millions of sequences and data volumes of the order of 3 TeraBytes. The modified pipeline, which we call DPCfam, finds ∼ 45,000 protein clusters in UniRef50. Our automatic classification is in close correspondence to the ones of the Pfam and ECOD resources: in particular, about 81% of medium-large Pfam families and 80% of ECOD families can be mapped to clusters generated by DPCfam. In addition, our protocol finds more than 14,000 clusters constituted of protein regions with no Pfam annotation, which are therefore candidates for representing novel protein families. These results are made available to the scientific community through a dedicated repository.

Technological advances in massively parallel sequencing have led to an exponential growth in the number of known protein sequences. Much of this growth originates from metagenomic projects producing new sequences from environmental and clinical samples. The Unified Human Gastrointestinal Proteome (UHGP) catalogue is one of the most relevant metagenomic datasets with applications ranging from medicine to biology. However, the lack of sequence annotation impairs its usability. This work aims to produce a family classification of UHGP sequences to facilitate downstream structural and functional annotation. This is achieved through the release of theDPCfam-UHGP50 datasetcontaining 10,778 putative protein families generated using DPCfam clustering, an unsupervised pipeline grouping sequences into multi-domain architectures. DPCfam-UHGP50 considerably improves family coverage at protein and residue levels compared to the manually curated repository Pfam. It is our hope that DPCfam-UHGP50 will foster future discoveries in the field of metagenomics of the human gut by the release of a FAIR-compliant database easily accessible via a searchable web server and Zenodo repository.