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Here, we investigate how the SARS-CoV-2 spike protein interacts with host cell membranes, focusing on a membrane-binding peptide (MBP) located near the TMPRSS2 cleavage site. Through in vitro and computational studies, we examine both primed (TMPRSS2-cleaved) and unprimed versions of the MBP, as well as the influence of its conserved disulfide bridge on membrane binding. Our results show that the MBP preferentially associates with cholesterol-rich membranes, and we find that cholesterol depletion significantly reduces viral infectivity. Furthermore, we observe that the disulfide bridge stabilizes the MBP\u2019s interaction with the membrane, suggesting a structural role in viral entry. Together, these findings highlight the importance of membrane composition and peptide structure in SARS-CoV-2 infectivity and suggest that targeting the disulfide bridge could provide a therapeutic strategy against infection.<\/jats:p>","DOI":"10.1038\/s41467-024-55358-9","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:04:15Z","timestamp":1735862655000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Probing SARS-CoV-2 membrane binding peptide via single-molecule AFM-based force spectroscopy"],"prefix":"10.1038","volume":"16","author":[{"given":"Qingrong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raissa S. 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