Probing SARS-CoV-2 membrane binding peptide via single-molecule AFM-based force spectroscopy

Qingrong Zhang, Raissa S. L. Rosa, Ankita Ray, Kimberley Durlet, Gol Mohammad Dorrazehi, Rafael C. Bernardi () and David Alsteens ()
Additional contact information
Qingrong Zhang: L7.07.07
Raissa S. L. Rosa: Auburn University
Ankita Ray: L7.07.07
Kimberley Durlet: L7.07.07
Gol Mohammad Dorrazehi: L7.07.07
Rafael C. Bernardi: Auburn University
David Alsteens: L7.07.07

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The SARS-CoV-2 spike protein’s membrane-binding domain bridges the viral and host cell membrane, a critical step in triggering membrane fusion. 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’s 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.

Date: 2025
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DOI: 10.1038/s41467-024-55358-9

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