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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,27]]},"abstract":"<jats:p>One of the key events in the HIV-1 life cycle is reverse transcription (RT), during which single-stranded viral RNA (ssRNA) is converted into double-stranded DNA (dsDNA). This process occurs inside the mature HIV-1 capsid and, once it reaches a critical threshold, drives capsid rupture. This uncoating is essential for infection because it releases viral genetic material into the host cell nucleus. Despite its importance, many mechanistic details of this process remain to be fully understood. To address this gap, we develop a multiscale computational method for simulating RT inside the capsid, termed Coarse-Grained Kinetic Monte Carlo (CG-KMC). CG-KMC stochastically adds deoxynucleotide triphosphates (dNTPs) to the coarse-grained RNA model, enabling stepwise growth of DNA inside the HIV-1 capsid. We implement this method within an integrative coarse-grained framework that combines a \u201cbottom-up\u201d capsid model with a \u201ctop-down\u201d representation of the viral RNA\/DNA genome. Our simulations phenomenologically capture and predict diverse capsid rupture pathways during RT. The resulting ruptured structures closely match previously identified cryo-ET images. We further perform an extensive analysis of the rupture process, examining its mechanistic and kinetic aspects as well as the role of capsid\u2013DNA interactions. Our findings illuminate how different capsid\u2013DNA conditions give rise to distinct rupture pathways, which differ from ruptures due to simple outward pressure expansion models from within the capsid.<\/jats:p>","DOI":"10.1073\/pnas.2617714123","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T18:01:52Z","timestamp":1792519312000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Mechanism of HIV-1 capsid rupture and uncoating by reverse transcription"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4935-3586","authenticated-orcid":false,"given":"Kuntal","family":"Ghosh","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/024mw5h28","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, Chicago Center for Theoretical Chemistry, James Franck Institute, and Institute for Biophysical Dynamics, The University 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