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Adv."],"published-print":{"date-parts":[[2026,3,20]]},"abstract":"<jats:p>By combining hydrogen-deuterium exchange monitored by mass spectrometry (HDX-MS) with the ability of enveloped virus\u2013like particles (eVLPs) to display full-length native-like severe acute respiratory syndrome coronavirus 2 spike protein, we have determined the energetic and conformational effects of both the membrane environment and unique sequence features that are considered incompatible with soluble protein constructs. We find that eVLP-displayed spike can sample the open-interface trimer conformation observed in soluble constructs of spike, including sequences from engineered vaccine constructs and native viral sequences inaccessible to studies on soluble constructs. Moreover, the D614G mutation, which arose early in the pandemic, favors the canonical \u201cclosed-interface\u201d prefusion conformation, potentially mitigating premature S1 shedding in the presence of a cleaved furin site and providing an evolutionary advantage to the virus. Furin cleavage at the S1\/S2 boundary allosterically increases the flexibility of the S2\u2032 site, which may facilitate increased TMPRSS2 processing, enhancing viral infectivity. The use of eVLPs in HDX-MS studies provides a powerful platform for studying viral and membrane proteins in near-native environments.<\/jats:p>","DOI":"10.1126\/sciadv.adx5178","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T18:01:06Z","timestamp":1774029666000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":1,"title":["Conformational dynamics of SARS-CoV-2 spike on a membrane reveals the allosteric effects of furin cleavage and the D614G mutation"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5278-2361","authenticated-orcid":true,"given":"Sophie R.","family":"Shoemaker","sequence":"first","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3327-7948","authenticated-orcid":true,"given":"Megan","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1416-4757","authenticated-orcid":true,"given":"Kim-Marie A.","family":"Dam","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Virology, San Francisco, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2998-9735","authenticated-orcid":true,"given":"John E.","family":"Pak","sequence":"additional","affiliation":[{"name":"Chan Zuckerberg Biohub\u2013San Francisco, San Francisco, CA, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-9568","authenticated-orcid":true,"given":"Magnus A. 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