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Advances in soluble gp140 trimer design have provided insight into the ectodomain structure and dynamics. While structural information is available for the membrane-proximal external region (MPER) and transmembrane domain (TMD), these regions remain comparatively understudied. Furthermore, high-resolution structural information for the cytoplasmic tail (CT), particularly within the context of the intact trimer, is limited and largely uncertain. Additionally, previous studies have typically treated the ectodomain and TMD as separate entities. To investigate the trimeric gp120\u2013gp41 as a complete entity and its structural flexibility, we built a full-length model of the gp120\u2013gp41 trimer that is fully glycosylated with N-linked glycans and embedded in a lipid bilayer, and performed all-atom molecular dynamics simulations. Our results show that the ectodomain maintains a rigid internal structure stable in the prefusion state, whereas the intrinsic flexibility of the MPER enables the ectodomain to adopt a range of tilted orientations, potentially enhancing spatial alignment for receptor engagement. The centrally positioned R696 residue in the TMD interacts with lipid headgroups, ions, and CT residues, resulting in conformational variability in the TMD and perturbations in the surrounding membrane that may facilitate the fusion process. Finally, we demonstrate how simulation trajectories can be leveraged to evaluate the accessibility of antibody epitopes across different regions of the protein.<\/jats:p>","DOI":"10.7554\/elife.110107","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T15:45:33Z","timestamp":1768319133000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110107","source":"Crossref","is-referenced-by-count":0,"title":["Conformational variability of HIV-1 Env trimer and viral vulnerability"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4516-8689","authenticated-orcid":true,"given":"Yiwei","family":"Cao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012afjb06","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, Lehigh University","place":["Bethlehem, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5642-6041","authenticated-orcid":true,"given":"Wonpil","family":"Im","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/012afjb06","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences, Lehigh University","place":["Bethlehem, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"20234","DOI":"10.1073\/pnas.0908713106","type":"journal-article","article-title":"Role of HIV membrane in neutralization by two broadly neutralizing antibodies","volume":"106","author":"Alam","year":"2009","journal-title":"PNAS"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"5181","DOI":"10.1073\/pnas.90.11.5181","type":"journal-article","article-title":"Lipid composition and fluidity of the human immunodeficiency virus envelope and host cell plasma membranes","volume":"90","author":"Aloia","year":"1993","journal-title":"PNAS"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"12999","DOI":"10.1074\/jbc.M115.644351","type":"journal-article","article-title":"The atomic structure of the HIV-1 gp41 transmembrane domain and its connection to the immunogenic membrane-proximal external region","volume":"290","author":"Apell\u00e1niz","year":"2015","journal-title":"The Journal of Biological Chemistry"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"13590","DOI":"10.1021\/jp507027t","type":"journal-article","article-title":"Dynamics of lipids, cholesterol, and transmembrane \u03b1-helices from microsecond molecular dynamics simulations","volume":"118","author":"Baker","year":"2014","journal-title":"The Journal of Physical Chemistry. 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