{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T20:12:13Z","timestamp":1778271133450,"version":"3.51.4"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>HIV-1 protease (PR) is an essential enzyme in the viral life cycle and a primary target of antiretroviral therapies, particularly protease inhibitors (PIs). Understanding the dynamics of viral evolution and the factors governing the emergence or loss of resistance-associated mutations is critical for improving PI efficacy and managing drug resistance in HIV\/AIDS treatment. In this study, we investigated the impact of three natural HIV-1 polymorphisms (T12A, L63Q, and H69N), whose prevalence varies depending on treatment status and viral subtype, on the structural stability and conformational dynamics of PR using molecular dynamics (MD) simulations. Three independent 500 ns MD simulations were performed for the native protease and each mutant system. Although none of the mutations disrupts the overall structural integrity of HIV-1 PR, they induce mutation-specific alterations in flexibility and residue interactions. In particular, T12A and H69N exhibit increased structural deviations, especially in the flap regions, along with enhanced conformational fluctuations. In contrast, the L63Q mutation shows a slight reduction in flap flexibility compared to both the native protease and the other mutants. Consistently, the fraction of time spent in open-flap conformations is higher for T12A and H69N and lower for L63Q relative to the native system. Moreover, mutations in the Fulcrum (T12A) and Cantilever (L63Q and H69N) regions do not disrupt the long-range network of correlated motions observed in the native protease, both inter- and intra-monomer, but instead increase the extent of correlated and anti-correlated motions in other regions of PR.<\/jats:p>","DOI":"10.3390\/ijms27093832","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unveiling the Impact of Drug-Sensitive Mutations on HIV-1 Protease Dynamics: A Molecular Dynamics Simulation Study of the T12A, L63Q, and H69N Variants"],"prefix":"10.3390","volume":"27","author":[{"given":"Haythem","family":"Srihi","sequence":"first","affiliation":[{"name":"Research Unit UR17ES30 \u201cGenomics, Biotechnology and Antiviral Strategies\u201d, High Institute of Biotechnology of Monastir, University of Monastir, Tahar Hadded Avenue, PB 74, Monastir 5000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nabil","family":"Abid","sequence":"additional","affiliation":[{"name":"High Institute of Biotechnology of Monastir, Department of Molecular and Cellular Biology, University of Monastir, Tahar Hadded Avenue, BP 74, Monastir 5000, Tunisia"},{"name":"Laboratory of Transmissible Diseases and Biological Active Substances LR99ES27, Faculty of Pharmacy, University of Monastir, Rue Ibn Sina, Monastir 5000, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-8611","authenticated-orcid":false,"given":"Lavinia","family":"Fabeni","sequence":"additional","affiliation":[{"name":"Laboratory of Virology, National Institute for Infectious Diseases Lazzaro Spallanzani\u2014IRCCS, Via Portuense, 292, 00149 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2565-8026","authenticated-orcid":false,"given":"Caterina","family":"Precone","sequence":"additional","affiliation":[{"name":"Department for Innovation in Biological, Agro-Food and Forest Systems\u2014DIBAF, University of Tuscia, 01100 Viterbo, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7531-4309","authenticated-orcid":false,"given":"H\u00e9l\u00e8ne","family":"D\u00e9m\u00e9n\u00e9","sequence":"additional","affiliation":[{"name":"Centre de Biochimie Structurale (CBS), INSERM, CNRS, Universit\u00e9 de Montpellier, 29 Rue de Navacelles, 34090 Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-6926","authenticated-orcid":false,"given":"Giovanni","family":"Chillemi","sequence":"additional","affiliation":[{"name":"Bioinformatics Research Unit in Infectious Diseases, National Institute for Infectious Diseases Lazzaro Spallanzani\u2014IRCCS, Via Portuense, 292, 00149 Rome, Italy"},{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16948","DOI":"10.1016\/S0021-9258(19)84799-3","article-title":"Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase","volume":"264","author":"Bebenek","year":"1989","journal-title":"J. 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