{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:33Z","timestamp":1760060793434,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Spanish Ministry of Science, Innovation and Universities","doi-asserted-by":"publisher","award":["PID2021-122216OB-I00"],"award-info":[{"award-number":["PID2021-122216OB-I00"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Given the limited knowledge of the effect of post-translational modifications (PTMs) on protein structure, in this study we investigated whether introducing one-to-three RA-related PTMs into the \u03b1-fibrin (617\u2013631) peptide influences the conformation and structure of the peptide antigen that could be responsible for the autoantibody recognition. Ten peptides containing a different number of PTMs within their primary structure were synthesized and their recognition by sera from RA patients was analyzed. The conformation of the peptides was studied by circular dichroism (CD) and the structure of the most relevant antigenic peptides was determined by nuclear magnetic resonance (NMR) and enhanced-sampling molecular dynamics (MD). Although peptides containing citrulline (Cit) showed a higher degree of binding to AMPAs than peptides containing only homocitrulline and\/or acetyl-lysine, the latter were able to bind to AMPAs in sera that showed a small response to peptides with Cit, with the response being different depending on the position of each PTM. CD and NMR analyses indicated a series of half-turn conformations in the Lys620-Arg630 region. MD simulations generated a set of conformations compatible with the NMR NOEs. The effect of the PTMs was observed in intra-molecular contacts, hydrogen bonds and van der Waals interactions, generating more collapsed conformations. Differences in autoantibody reactivity between peptides bearing different PTMs within their primary structures are noted. Peptides with PTMs adopt different conformations than unmodified peptides, probably due to the lower net charge of peptides with multiple PTMs, which may explain their recognition by autoantibodies.<\/jats:p>","DOI":"10.3390\/ijms26189026","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:59:51Z","timestamp":1758088791000},"page":"9026","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Structural Study of a Peptide Epitope Bearing Multiple Post-Translational Modifications in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6906-4833","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"G\u00f3mara","sequence":"first","affiliation":[{"name":"Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Garc\u00eda-Moreno","sequence":"additional","affiliation":[{"name":"Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8439-4005","authenticated-orcid":false,"given":"Oriol","family":"B\u00e1rcenas","sequence":"additional","affiliation":[{"name":"Computational and Theoretical Chemistry Group, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain"},{"name":"Institut de Biotecnologia i de Biomedicina and Departament de Bioqu\u00edmica i Biologia Molecular, Universitat Aut\u00f2noma de Barcelona, 08193 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ra\u00fal","family":"Castellanos-Moreira","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital Cl\u00ednic of Barcelona, 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8426-7268","authenticated-orcid":false,"given":"Juan Camilo","family":"Sarmiento","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital Cl\u00ednic of Barcelona, 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6687-382X","authenticated-orcid":false,"given":"Ramon","family":"Crehuet","sequence":"additional","affiliation":[{"name":"Computational and Theoretical Chemistry Group, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-5346","authenticated-orcid":false,"given":"Yolanda","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"NMR Facility, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raimon","family":"Sanmart\u00ed","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital Cl\u00ednic of Barcelona, 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8677-2340","authenticated-orcid":false,"given":"Isabel","family":"Haro","sequence":"additional","affiliation":[{"name":"Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Jordi Girona 18-26, 08034 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.2174\/15680266113139990091","article-title":"Rheumatoid arthritis: Current advances in pathogenesis, diagnosis and therapy","volume":"13","author":"Haro","year":"2013","journal-title":"Curr. 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