{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T05:03:53Z","timestamp":1780981433992,"version":"3.54.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1013431","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000}}],"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM147367"],"award-info":[{"award-number":["GM147367"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["1K99AI180984-01A1"],"award-info":[{"award-number":["1K99AI180984-01A1"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2224128"],"award-info":[{"award-number":["2224128"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I-1505"],"award-info":[{"award-number":["I-1505"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I-2095-20220331"],"award-info":[{"award-number":["I-2095-20220331"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NSF ACCESS","award":["BIO250039"],"award-info":[{"award-number":["BIO250039"]}]},{"name":"NSF ACCESS","award":["MED240004"],"award-info":[{"award-number":["MED240004"]}]},{"name":"Texas Advanced Computing Center","award":["MCB24018"],"award-info":[{"award-number":["MCB24018"]}]},{"name":"Texas Advanced Computing Center","award":["MCB23014"],"award-info":[{"award-number":["MCB23014"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The development of highly accurate protein structure prediction algorithms has led to an explosion of structural data, transforming our understanding of protein structure-function relationships across diverse organisms. Domain classifications such as the Evolutionary Classification of Protein Domains (ECOD) have incorporated these computational predictions alongside experimental structures to create comprehensive resources for the research community. The AlphaFold Protein Structure Database (AFDB) plays a unique role, providing millions of predicted structures that ECOD has systematically classified for human proteins, small pathogens, and reference proteomes. Here, we extend this classification framework to the UniProtKB\/Swiss-Prot dataset, applying the Domain Parser for AlphaFold Models (DPAM) pipeline to classify domains from over 542,000 Swiss-Prot protein structure predictions, resulting in more than 1,032,000 classified domains. These domains span 3,493 ECOD topologies and display high assignment confidence (mean DPAM probability: 0.992), with extensive taxonomic and functional diversity. Notably, over 100,000 domains lack existing Pfam mappings, reflecting the extended sensitivity of structure-based classification and identifying domain groups not yet captured by sequence-based profiles. These results significantly expand ECOD\u2019s coverage into a functionally and taxonomically diverse protein space, anchoring high-confidence structure predictions in an evolutionary framework. By integrating Swiss-Prot predictions, we enhance the utility and interpretability of AlphaFold models and establish a foundation for future large-scale, functionally informed domain classifications.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013431","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T17:31:28Z","timestamp":1774891888000},"page":"e1013431","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["ECOD: Classification of domains in AFDB Swiss-Prot structure predictions"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6502-1425","authenticated-orcid":true,"given":"R. Dustin","family":"Schaeffer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Cong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick V.","family":"Grishin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"issue":"1","key":"pcbi.1013431.ref001","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1042\/BJ20090122","article-title":"Genomic and structural aspects of protein evolution","volume":"419","author":"C Chothia","year":"2009","journal-title":"Biochem J"},{"key":"pcbi.1013431.ref002","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1146\/annurev.bi.64.070195.001443","article-title":"The multiplicity of domains in proteins","volume":"64","author":"RF Doolittle","year":"1995","journal-title":"Annu Rev Biochem"},{"issue":"1","key":"pcbi.1013431.ref003","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12862-020-1591-0","article-title":"The modular nature of protein evolution: domain rearrangement rates across eukaryotic life","volume":"20","author":"E Dohmen","year":"2020","journal-title":"BMC Evol Biol"},{"issue":"2","key":"pcbi.1013431.ref004","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1093\/bioinformatics\/bts682","article-title":"Defining and predicting structurally conserved regions in protein superfamilies","volume":"29","author":"IK Huang","year":"2013","journal-title":"Bioinformatics"},{"key":"pcbi.1013431.ref005","article-title":"TMEM120A is a coenzyme A-binding membrane protein with structural similarities to ELOVL fatty acid elongase","volume":"10","author":"J Xue","year":"2021","journal-title":"Elife"},{"issue":"12","key":"pcbi.1013431.ref006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1007569","article-title":"Functional analysis of Rossmann-like domains reveals convergent evolution of topology and reaction pathways","volume":"15","author":"KE Medvedev","year":"2019","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"pcbi.1013431.ref007","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/prot.10110","article-title":"Expanding the nitrogen regulatory protein superfamily: Homology detection at below random sequence identity","volume":"48","author":"LN Kinch","year":"2002","journal-title":"Proteins"},{"issue":"2","key":"pcbi.1013431.ref008","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/prot.22447","article-title":"The Rho GTPase inactivation domain in Vibrio cholerae MARTX toxin has a circularly permuted papain-like thiol protease fold","volume":"77","author":"J Pei","year":"2009","journal-title":"Proteins"},{"key":"pcbi.1013431.ref009","article-title":"The Pfam protein families database: embracing AI\/ML","author":"T Paysan-Lafosse","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref010","article-title":"The conserved domain database in 2023","volume":"51","author":"J Wang","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref011","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gky1130","article-title":"The SUPERFAMILY 2.0 database: a significant proteome update and a new webserver","volume":"47","author":"AP Pandurangan","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref012","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkz1064","article-title":"The SCOP database in 2020: expanded classification of representative family and superfamily domains of known protein structures","volume":"48","author":"A Andreeva","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref013","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae1087","article-title":"CATH v4.4: major expansion of CATH by experimental and predicted structural data","volume":"53","author":"VP Waman","year":"2025","journal-title":"Nucleic Acids Research"},{"key":"pcbi.1013431.ref014","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae1029","article-title":"ECOD: integrating classifications of protein domains from experimental and predicted structures","volume":"53","author":"RD Schaeffer","year":"2025","journal-title":"Nucleic Acids Res"},{"issue":"12","key":"pcbi.1013431.ref015","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1002\/prot.26257","article-title":"Applying and improving AlphaFold at CASP14","volume":"89","author":"J Jumper","year":"2021","journal-title":"Proteins"},{"issue":"6557","key":"pcbi.1013431.ref016","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction of protein structures and interactions using a three-track neural network","volume":"373","author":"M Baek","year":"2021","journal-title":"Science"},{"issue":"6637","key":"pcbi.1013431.ref017","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1126\/science.ade2574","article-title":"Evolutionary-scale prediction of atomic-level protein structure with a language model","volume":"379","author":"Z Lin","year":"2023","journal-title":"Science"},{"issue":"8016","key":"pcbi.1013431.ref018","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"J Abramson","year":"2024","journal-title":"Nat"},{"key":"pcbi.1013431.ref019","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"M Varadi","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref020","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkad1011","article-title":"AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences","volume":"52","author":"M Varadi","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"12","key":"pcbi.1013431.ref021","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2214069120","article-title":"Classification of domains in predicted structures of the human proteome","volume":"120","author":"RD Schaeffer","year":"2023","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pcbi.1013431.ref022","doi-asserted-by":"crossref","DOI":"10.1128\/msystems.00796-23","article-title":"Insights into virulence: structure classification of the Vibrio parahaemolyticus RIMD mobilome","volume":"8","author":"LN Kinch","year":"2023","journal-title":"mSystems"},{"issue":"1","key":"pcbi.1013431.ref023","doi-asserted-by":"crossref","first-page":"12260","DOI":"10.1038\/s41598-024-60991-x","article-title":"Structure classification of the proteins from Salmonella enterica pangenome revealed novel potential pathogenicity islands","volume":"14","author":"KE Medvedev","year":"2024","journal-title":"Sci Rep"},{"issue":"2","key":"pcbi.1013431.ref024","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1011586","article-title":"ECOD domain classification of 48 whole proteomes from AlphaFold Structure Database using DPAM2","volume":"20","author":"RD Schaeffer","year":"2024","journal-title":"PLoS Comput Biol"},{"issue":"6721","key":"pcbi.1013431.ref025","article-title":"Exploring structural diversity across the protein universe with The Encyclopedia of Domains","volume":"386","author":"AM Lau","year":"2024","journal-title":"Science"},{"key":"pcbi.1013431.ref026","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkae1010","article-title":"UniProt: the Universal Protein Knowledgebase in 2025","volume":"53","author":"UniProt Consortium","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref027","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkx1069","article-title":"Gene3D: Extensive prediction of globular domains in proteins","volume":"46","author":"TE Lewis","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref028","article-title":"New and continuing developments at PROSITE","volume":"41","author":"CJA Sigrist","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1013431.ref029","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gku1221","article-title":"CDD: NCBI\u2019s conserved domain database","volume":"43","author":"A Marchler-Bauer","year":"2015","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pcbi.1013431.ref030","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1093\/nar\/28.1.304","article-title":"The ENZYME database in 2000","volume":"28","author":"A Bairoch","year":"2000","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pcbi.1013431.ref031","doi-asserted-by":"crossref","DOI":"10.1093\/genetics\/iyad031","article-title":"The Gene Ontology knowledgebase in 2023","volume":"224","author":"Gene Ontology Consortium","year":"2023","journal-title":"Genetics"},{"issue":"1","key":"pcbi.1013431.ref032","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: tool for the unification of biology","volume":"25","author":"M Ashburner","year":"2000","journal-title":"Nat Genet"},{"key":"pcbi.1013431.ref033","author":"J Zhang","year":"2022"},{"issue":"12","key":"pcbi.1013431.ref034","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1002\/bip.360221211","article-title":"Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features","volume":"22","author":"W Kabsch","year":"1983","journal-title":"Biopolymers"},{"key":"pcbi.1013431.ref035","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkq1105","article-title":"A series of PDB related databases for everyday needs","volume":"39","author":"RP Joosten","year":"2011","journal-title":"Nucleic Acids Res"},{"issue":"13","key":"pcbi.1013431.ref036","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1093\/bioinformatics\/btl158","article-title":"Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences","volume":"22","author":"W Li","year":"2006","journal-title":"Bioinformatics"},{"issue":"1","key":"pcbi.1013431.ref037","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1093\/bioinformatics\/18.1.77","article-title":"Tolerating some redundancy significantly speeds up clustering of large protein databases","volume":"18","author":"W Li","year":"2002","journal-title":"Bioinformatics"},{"issue":"3","key":"pcbi.1013431.ref038","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/bioinformatics\/17.3.282","article-title":"Clustering of highly homologous sequences to reduce the size of large protein databases","volume":"17","author":"W Li","year":"2001","journal-title":"Bioinformatics"},{"issue":"10","key":"pcbi.1013431.ref039","article-title":"Accelerated Profile HMM Searches","volume":"7","author":"SR Eddy","year":"2011","journal-title":"PLoS Comput Biol"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1013431","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T00:00:00Z","timestamp":1775174400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:56:05Z","timestamp":1775238965000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013431"}},"subtitle":[],"editor":[{"given":"Chaok","family":"Seok","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013431","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]}}}