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As the primary component of tendons, ligaments, and other connective tissues, it has to withstand extreme forces. Base-catalyzed peptide hydrolysis was recently shown to be greatly accelerated by mechanical force. This puts collagen at risk of degradation under physiological loads, yet collagen is known to be remarkably stable. Using hybrid quantum mechanics\/molecular mechanics (QM\/MM) simulations, we investigated the hydrolysis reaction within the complex chemical environment of a collagen triple helix. We demonstrate that the unique triple-helical structure increases the reaction barrier for base-catalyzed hydrolysis compared to a single peptide chain. Our results can explain why collagen mechanical failure proceeds through homolytic bond rupture and mechanoradical formation.<\/jats:p>","DOI":"10.1021\/acsomega.6c05284","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T22:02:05Z","timestamp":1786399325000},"page":"51498-51509","source":"Crossref","is-referenced-by-count":0,"title":["Collagen\u2019s\nTriple Helix Reduces the Susceptibility\nto Base-Catalyzed Hydrolysis"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9350-2629","authenticated-orcid":true,"given":"Jannik","family":"Buhr","sequence":"first","affiliation":[{"name":"Heidelberg Institute for Theoretical Studies , Am Schloss-Wolfsbrunnenweg 35 , ,","place":["Heidelberg, Germany, 69117"]},{"name":"Heidelberg University , , Im Neuenheimer Feld 205 , ,","place":["Heidelberg, Germany, 69120"]},{"name":"Max Planck Institute for Polymer Research , Ackermannweg 10 , ,","place":["Mainz, Germany, 55128"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2891-3381","authenticated-orcid":true,"given":"Frauke","family":"Gra\u0308ter","sequence":"additional","affiliation":[{"name":"Heidelberg Institute for Theoretical Studies , Am Schloss-Wolfsbrunnenweg 35 , ,","place":["Heidelberg, Germany, 69117"]},{"name":"Heidelberg University , , Im Neuenheimer Feld 205 , ,","place":["Heidelberg, Germany, 69120"]},{"name":"Max Planck Institute for Polymer Research , Ackermannweg 10 , ,","place":["Mainz, Germany, 55128"]},{"name":"Max Planck School Matter to Life , Jahnstra\u00dfe 29 , ,","place":["Heidelberg, Germany, 69120"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"2026090307183146600_cit1","article-title":"\u201cAging\nof the Collagen Fiber\u201d","volume-title":"International\nReview of Connective Tissue Research","author":"Verza\u0301r","year":"1964"},{"key":"2026090307183146600_cit2","unstructured":"Fratzl, P.\n          \n          \u201cCollagen:\nStructure and Mechanics, an Introduction\u201d\n          2008\n          10.1007\/978-0-387-73906-9_1."},{"key":"2026090307183146600_cit3","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","article-title":"Collagen Structure and Stability","volume":"78","author":"Shoulders","year":"2009","journal-title":"Annu. 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