{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:18:21Z","timestamp":1789395501118,"version":"build-2803163510"},"reference-count":51,"publisher":"American Chemical Society (ACS)","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100002338","name":"Ministry of Education of the People's Republic of China","doi-asserted-by":"publisher","award":["JYB2025XDXM507"],"award-info":[{"award-number":["JYB2025XDXM507"]}],"id":[{"id":"10.13039\/501100002338","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lab of Computational Chemistry and Drug Design, Shenzhen","award":["SYSPG20241211173440006"],"award-info":[{"award-number":["SYSPG20241211173440006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Specific recognition between T-cell receptors (TCRs) and peptide\u2013major histocompatibility complexes (pMHCs) is central to adaptive immunity, yet accurate prediction of TCR\u2013pMHC specificity remains challenging. Existing models mainly rely on sequence features or isolated molecular structures, limiting their ability to capture interface-level determinants within the ternary recognition complex. Here, we constructed the multimodal TCR\u2013pMHC ternary complex (MM-TCR) data set, integrating paired TCR\u2013pMHC sequences, V\/J gene annotations, and modeled TCR\u2013pMHC complex structures refined by short molecular dynamics-based relaxation. Based on MM-TCR, we developed TCRspec, an interpretable multimodal framework combining sequence embeddings, gene-usage features, and complex-level structural representations. Under a stringent CD-HIT TCR-cluster-disjoint split, TCRspec achieved an average AUROC of 0.896 and AUPRC of 0.882 across seven antigen-specific test data sets, outperforming representative baseline models. Cross-validation and ablation analyses confirmed the contribution of ternary complex structural information and MD-refined structures. In independent OOD peptide\u2013TCR systems, TCRspec retained discriminative performance and identified model-inferred peptide positions associated with TCR recognition, providing a structure-informed framework for TCR specificity prediction.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01399","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:34:44Z","timestamp":1788327284000},"page":"10622-10634","source":"Crossref","is-referenced-by-count":0,"title":["TCRspec: A Recognition\nInterface-Informed Multimodal\nMethod for TCR\u2013pMHC Specificity Prediction"],"prefix":"10.1021","volume":"66","author":[{"given":"Jia-Ling","family":"Zou","sequence":"first","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]},{"name":"Tianmu Institute of Health , ,","place":["Changzhou, China, 213399"]},{"name":"Shenzhen Bay Laboratory , ,","place":["Shenzhen, China, 518132"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zong-Ying","family":"Lin","sequence":"additional","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]},{"name":"Guangdong Provincial Key Laboratory of AI for Science, Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Mi","family":"Wang","sequence":"additional","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]},{"name":"Guangdong Provincial Key Laboratory of AI for Science, Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7883-8886","authenticated-orcid":true,"given":"Shu","family":"Yang","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yuan","sequence":"additional","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9213-9832","authenticated-orcid":true,"given":"Calvin","family":"Yu-Chian Chen","sequence":"additional","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Hong","family":"Tian","sequence":"additional","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]},{"name":"Guangdong Provincial Key Laboratory of AI for Science, Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4477-7332","authenticated-orcid":true,"given":"Yun-Dong","family":"Wu","sequence":"additional","affiliation":[{"name":"Peking University Shenzhen Graduate School , ,","place":["Shenzhen, China, 518055"]},{"name":"Shenzhen Bay Laboratory , ,","place":["Shenzhen, China, 518132"]},{"name":"Peking University , , ,","place":["Beijing, China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"2026091409062724400_cit1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0092-8674(01)00185-4","article-title":"T cell receptor-MHC interactions up close","volume":"104","author":"Hennecke","year":"2001","journal-title":"Cell"},{"key":"2026091409062724400_cit2","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/s41577-021-00574-3","article-title":"CD8+ T cell\ndifferentiation and dysfunction in cancer","volume":"22","author":"Philip","year":"2022","journal-title":"Nat.\nRev. Immunol."},{"key":"2026091409062724400_cit3","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nrrheum.2016.74","article-title":"CD8+ T cells in human\nautoimmune arthritis: the unusual\nsuspects","volume":"12","author":"Petrelli","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"2026091409062724400_cit4","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1038\/s41571-021-00573-2","article-title":"Immunotherapies for hepatocellular carcinoma","volume":"19","author":"Llovet","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"2026091409062724400_cit5","doi-asserted-by":"publisher","first-page":"12472","DOI":"10.18632\/oncotarget.2998","article-title":"Classification of current\nanticancer immunotherapies","volume":"5","author":"Galluzzi","year":"2014","journal-title":"Oncotarget"},{"key":"2026091409062724400_cit6","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/s41592-018-0304-8","article-title":"T cell antigen discovery via signaling and\nantigen-presenting bifunctional\nreceptors","volume":"16","author":"Joglekar","year":"2019","journal-title":"Nat. Methods"},{"key":"2026091409062724400_cit7","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s41568-021-00346-0","article-title":"Therapeutic\ncancer\nvaccines","volume":"21","author":"Saxena","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"2026091409062724400_cit8","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/s41416-020-01048-4","article-title":"Cytotoxic\nCD8+ T cells in cancer and cancer immunotherapy","volume":"124","author":"Raskov","year":"2021","journal-title":"Br. J. Cancer"},{"key":"2026091409062724400_cit9","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1007\/s00428-018-2484-0","article-title":"Adoptive cellular therapies: the\ncurrent landscape","volume":"474","author":"Rohaan","year":"2019","journal-title":"Virchows Arch."},{"key":"2026091409062724400_cit10","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1158\/2159-8290.CD-18-0367","article-title":"Fundamental\nmechanisms of immune\ncheckpoint blockade therapy","volume":"8","author":"Wei","year":"2018","journal-title":"Cancer Discovery"},{"key":"2026091409062724400_cit11","doi-asserted-by":"publisher","first-page":"2952","DOI":"10.4049\/jimmunol.179.5.2952","article-title":"CD8+ T\ncell activation is governed by TCR-peptide\/MHC affinity, not dissociation\nrate","volume":"179","author":"Tian","year":"2007","journal-title":"J. Immunol."},{"key":"2026091409062724400_cit12","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1038\/nri.2017.131","article-title":"Towards personalized, tumour-specific,\ntherapeutic vaccines for cancer","volume":"18","author":"Hu","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"2026091409062724400_cit13","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/S0167-5699(98)01299-7","article-title":"A very\nhigh level of crossreactivity is an essential feature of the T-cell\nreceptor","volume":"19","author":"Mason","year":"1998","journal-title":"Immunol. Today"},{"key":"2026091409062724400_cit14","doi-asserted-by":"publisher","first-page":"1168","DOI":"10.1074\/jbc.M111.289488","article-title":"A single autoimmune T cell receptor recognizes\nmore than a million\ndifferent peptides","volume":"287","author":"Wooldridge","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026091409062724400_cit15","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/nsmb.3383","article-title":"Broad TCR repertoire and diverse structural solutions\nfor recognition\nof an immunodominant CD8+ T cell epitope","volume":"24","author":"Song","year":"2017","journal-title":"Nat.\nStruct. Mol. Biol."},{"key":"2026091409062724400_cit16","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1016\/j.it.2014.10.005","article-title":"Understanding\nthe structural dynamics\nof TCR-pMHC interactions","volume":"35","author":"Kass","year":"2014","journal-title":"Trends Immunol."},{"key":"2026091409062724400_cit17","first-page":"2021-10","article-title":"Protein\ncomplex prediction with alphafold-multimer","volume":"2021\u201310","author":"Evans","year":"2021","journal-title":"bioRxiv"},{"issue":"9","key":"2026091409062724400_cit18","article-title":"Thlanet: A deep learning\nframework for predicting TCR-pHLA\nbinding in immunotherapy applications","volume":"21","author":"Long","year":"2025","journal-title":"PLoS\nComputat.l Biol."},{"key":"2026091409062724400_cit19","doi-asserted-by":"publisher","first-page":"035005","DOI":"10.1088\/1478-3975\/10\/3\/035005","article-title":"Conserved variation: identifying patterns of stability\nand variability in BCR and TCR V genes with different diversity and\nrichness metrics","volume":"10","author":"Schwartz","year":"2013","journal-title":"Phys. Biol."},{"key":"2026091409062724400_cit20","doi-asserted-by":"publisher","first-page":"3477","DOI":"10.1016\/j.molimm.2007.10.016","article-title":"Computational characterization of B-cell epitopes","volume":"45","author":"Rubinstein","year":"2008","journal-title":"Mol. Immunol."},{"key":"2026091409062724400_cit21","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/1074-7613(95)90124-8","article-title":"New insights\ninto V (D) J recombination and its role in the evolution of the immune\nsystem","volume":"3","author":"Thompson","year":"1995","journal-title":"Immunity"},{"key":"2026091409062724400_cit22","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1038\/nature22991","article-title":"An immunogenic personal neoantigen vaccine for patients\nwith melanoma","volume":"547","author":"Ott","year":"2017","journal-title":"Nature"},{"key":"2026091409062724400_cit23","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1126\/science.274.5284.94","article-title":"Phenotypic analysis of antigen-specific T lymphocytes","volume":"274","author":"Altman","year":"1996","journal-title":"Science"},{"key":"2026091409062724400_cit24","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/j.cell.2014.03.047","article-title":"Deconstructing the peptide-MHC\nspecificity of T cell recognition","volume":"157","author":"Birnbaum","year":"2014","journal-title":"Cell"},{"key":"2026091409062724400_cit25","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nature22383","article-title":"Quantifiable predictive\nfeatures define epitope-specific t cell receptor\nrepertoires","volume":"547","author":"Dash","year":"2017","journal-title":"Nature"},{"key":"2026091409062724400_cit26","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1038\/nature22976","article-title":"Identifying specificity groups in the T cell receptor repertoire","volume":"547","author":"Glanville","year":"2017","journal-title":"Nature"},{"key":"2026091409062724400_cit27","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nature22383","article-title":"Quantifiable predictive\nfeatures define epitope-specific T cell receptor\nrepertoires","volume":"547","author":"Dash","year":"2017","journal-title":"Nature"},{"key":"2026091409062724400_cit28","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/s43588-021-00076-1","article-title":"Rapid assessment of T-cell receptor specificity of the immune repertoire","volume":"1","author":"Lin","year":"2021","journal-title":"Nat. Comput. Sci."},{"key":"2026091409062724400_cit29","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1038\/s42003-021-02610-3","article-title":"Nettcr-2.0 enables accurate prediction of TCR-peptide\nbinding by using paired TCR \u03b1 and \u03b2 sequence data","volume":"4","author":"Montemurro","year":"2021","journal-title":"Commun. Biol."},{"key":"2026091409062724400_cit30","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abf5835","article-title":"A framework\nfor highly multiplexed dextramer mapping\nand prediction of T cell receptor sequences to antigen specificity","volume":"7","author":"Zhang","year":"2021","journal-title":"Sci. Adv."},{"key":"2026091409062724400_cit31","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1038\/s41467-021-21879-w","article-title":"DeepTCR is a deep\nlearning framework for revealing sequence concepts within T-cell repertoires","volume":"12","author":"Sidhom","year":"2021","journal-title":"Nat. Commun."},{"key":"2026091409062724400_cit32","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20199416","article-title":"Predicting antigen specificity of\nsingle T cells based on TCR CDR 3 regions","volume":"16","author":"Fischer","year":"2020","journal-title":"Mol.\nSyst. Biol."},{"key":"2026091409062724400_cit33","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1038\/s42256-021-00383-2","article-title":"Deep learning-based\nprediction of the T cell receptor\u2013antigen\nbinding specificity","volume":"3","author":"Lu","year":"2021","journal-title":"Nature Machine Intelligence"},{"key":"2026091409062724400_cit34","doi-asserted-by":"publisher","first-page":"bbad086","DOI":"10.1093\/bib\/bbad086","article-title":"Teinet: a\ndeep learning framework for prediction of\nTCR\u2013epitope binding specificity","volume":"24","author":"Jiang","year":"2023","journal-title":"Briefings\nBioinf."},{"key":"2026091409062724400_cit35","doi-asserted-by":"publisher","first-page":"1614","DOI":"10.1038\/s41590-022-01337-5","article-title":"Divergent clonal differentiation trajectories of T\ncell exhaustion","volume":"23","author":"Daniel","year":"2022","journal-title":"Nat. Immunol."},{"key":"2026091409062724400_cit36","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo5128","article-title":"Deepair:\nA deep learning framework for effective integration of sequence and\n3D structure to enable adaptive immune receptor analysis","volume":"9","author":"Zhao","year":"2023","journal-title":"Sci. Adv."},{"key":"2026091409062724400_cit37","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with alphafold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"issue":"W1","key":"2026091409062724400_cit38","doi-asserted-by":"crossref","first-page":"W526","DOI":"10.1093\/nar\/gkae407","article-title":"Next-Generation\nIEDB Tools Website\nand api-release 1.1. Immune Epitope Database and Analysis Resource\n(IEDB)","volume":"52","author":"Yan","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"2026091409062724400_cit39","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/978-1-4939-7000-1_26","article-title":"Protein Data Bank (PDB): the single\nglobal macromolecular structure\narchive","volume-title":"Protein Crystallography: Methods\nand Protocols","author":"Burley","year":"2017"},{"key":"2026091409062724400_cit40","doi-asserted-by":"publisher","first-page":"3150","DOI":"10.1093\/bioinformatics\/bts565","article-title":"Cd-hit: accelerated\nfor clustering the next-generation sequencing data","volume":"28","author":"Fu","year":"2012","journal-title":"Bioinformatics"},{"key":"2026091409062724400_cit41","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/pro.2181","article-title":"Structure-based\nprediction of t cell receptor:peptide-mhc interactions","volume":"12","author":"Bradley","year":"2023","journal-title":"eLife"},{"key":"2026091409062724400_cit42","doi-asserted-by":"publisher","first-page":"4474","DOI":"10.1021\/acs.jctc.8b00285","article-title":"Universal implementation of a residue-specific\nforce field based on cmap potentials and free energy decomposition","volume":"14","author":"Kang","year":"2018","journal-title":"J. Chem. Theory Comput."},{"key":"2026091409062724400_cit43","doi-asserted-by":"publisher","DOI":"10.7554\/elife.82813","article-title":"Structure-based\nprediction of T cell receptor: peptide-MHC interactions","volume":"12","author":"Bradley","year":"2023","journal-title":"eLife"},{"key":"2026091409062724400_cit44","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1126\/science.ade2574","article-title":"Evolutionary-scale prediction\nof atomic-level protein structure with\na language model","volume":"379","author":"Lin","year":"2023","journal-title":"Science"},{"key":"2026091409062724400_cit45","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1146\/annurev-immunol-032414-112334","article-title":"T cell antigen receptor recognition of antigen-presenting molecules","volume":"33","author":"Rossjohn","year":"2015","journal-title":"Annu. Rev. Immunol."},{"key":"2026091409062724400_cit46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2023141118","article-title":"Deep generative\nselection models of T and B cell receptor repertoires with sonnia","volume":"118","author":"Isacchini","year":"2021","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2026091409062724400_cit47","doi-asserted-by":"publisher","first-page":"893247","DOI":"10.3389\/fimmu.2022.893247","article-title":"Atm-tcr: Tcr-epitope\nbinding affinity prediction using a multi-head self-attention model","volume":"13","author":"Cai","year":"2022","journal-title":"Front. Immunol."},{"key":"2026091409062724400_cit48","doi-asserted-by":"publisher","first-page":"1803","DOI":"10.3389\/fimmu.2020.01803","article-title":"Prediction\nof specific tcr-peptide binding from large dictionaries of tcr-peptide\npairs","volume":"11","author":"Springer","year":"2020","journal-title":"Front. Immunol."},{"key":"2026091409062724400_cit49","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/s41587-023-01773-0","article-title":"Fast and accurate protein structure search with foldseek","volume":"42","author":"Van Kempen","year":"2024","journal-title":"Nat. Biotechnol."},{"key":"2026091409062724400_cit50","first-page":"1","article-title":"A new way of exploring immunity\u2013linking\nhighly multiplexed antigen recognition to immune repertoire and phenotype","author":"Genomics.","year":"2019","journal-title":"Technol. Rep."},{"key":"2026091409062724400_cit51","doi-asserted-by":"publisher","first-page":"D419","DOI":"10.1093\/nar\/gkx760","article-title":"VDJdb: a curated database\nof T-cell receptor sequences with known\nantigen specificity","volume":"46","author":"Shugay","year":"2018","journal-title":"Nucleic Acids Res."}],"container-title":["Journal of Chemical Information\nand Modeling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.jcim.6c01399","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/10622\/67626435\/acs.jcim.6c01399.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article-pdf\/66\/17\/10622\/67626435\/acs.jcim.6c01399.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:30:22Z","timestamp":1789392622000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jcisd8\/article\/66\/17\/10622\/5351372\/TCRspec-A-Recognition-Interface-Informed"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":51,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,8,28]]},"published-print":{"date-parts":[[2026,9,14]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.jcim.6c01399","relation":{},"ISSN":["1549-9596","1549-960X"],"issn-type":[{"value":"1549-9596","type":"print"},{"value":"1549-960X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]}}}