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Activation of SARS-CoV-2 Spike deploys its fusion peptide to a membrane of the host cell to infect it. NMR in solution demonstrates that this fusion peptide transforms from intrinsic disorder in solution into a wedge-shaped structure inserted in bilayered micelles. According to NOEs and proximity to a nitroxide spin label deep in the membrane mimic, the globular fold of three helices contrasts the open, extended conformations observed in compact prefusion states. In the hydrophobic, narrow end of the wedge, helices 1 and 2 contact the fatty acyl chains of phospholipids. 50 of the resulting paramagnetic NMR relaxation enhancements and 6 lipid-protein NOEs provided ambiguous distances as collective variables (colvars) to bias and guide MD simulations. Simulations in NAMD using the CHARMM36 forcefield included colvars for 130 medium- and long-range NOEs to maintain the equilibrium structure. In the gently NMR-biased simulations, the fusion peptide maintained its insertion of helices 1 and 2 within a single leaflet while helix 3 remained exposed. A cation occasionally visited the anionic side chains in the loop joining helices 2 and 3 or at the N-terminal end of helix 1. The unoccupied leaflet is thinned and distorted opposite the fusion peptide.The thinning could be related to the fusion peptide promoting formation of the hemi-fusion intermediate in the process of viral-cell fusion. Supported by NSF Rapid award 2030473.
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This content will become publicly available on December 19, 2025
Exploring the influence of anionic lipids in the host cell membrane on viral fusion
Membrane fusion is an essential component of the viral lifecycle that allows the delivery of the genetic information of the virus into the host cell. Specialized viral glycoproteins exist on the surface of mature virions where they facilitate fusion through significant conformational changes, ultimately bringing opposing membranes into proximity until they eventually coalesce. This process can be positively influenced by a number of specific cellular factors such as pH, enzymatic cleavage, divalent ions, and the composition of the host cell membrane. In this review, we have summarized how anionic lipids have come to be involved in viral fusion and how the endosomal resident anionic lipid BMP has become increasingly implicated as an important cofactor for those viruses that fuse via the endocytic pathway.
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- Award ID(s):
- 2238139
- PAR ID:
- 10567789
- Publisher / Repository:
- Biochemical Society Transactions
- Date Published:
- Journal Name:
- Biochemical Society Transactions
- Volume:
- 52
- Issue:
- 6
- ISSN:
- 0300-5127
- Page Range / eLocation ID:
- 2593 to 2602
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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