Please refer to and cite this article in press at Structure:
SARS-CoV-2 Fusion Peptide Sculpting of a Membrane
with Insertion of Charged and Polar Groups
Steven R. Van Doren1,2,3,*, Benjamin S. Scott1, Rama K. Koppisetti1,4
1 Department of Biochemistry, University of Missouri, Columbia, MO 65211 USA
2 Institute for Data Science and Informatics, University of Missouri, Columbia, MO 65211 USA
3 Lead contact
4 Present Address: Rama K. Koppisetti, Washington University School of Medicine, St. Louis, MO 63110 United States
*Correspondence: vandorens@missouri.edu (S.R.V)
The preprint form of the manuscript, prior to revisions responding to peer review, is available as the *Structure* Sneak Peak (dated 12/29/22) at: https://papers.ssrn.com/sol3/cf_dev/AbsByAuth.cfm?per_id=5632766
Summary
The fusion peptide of SARS-CoV-2 Spike is essential for infection. How this charged and hydrophobic domain occupies and affects membranes needs clarification. Its depth in zwitterionic, bilayered micelles at pH 5 (resembling late endosomes) was measured by paramagnetic NMR relaxation enhancements used to bias molecular dynamics simulations. Asp830 inserted deeply, along with Lys825 or Lys835. Protonation of Asp830 appeared to enhance agreement of simulated and NMR-measured depths. While the fusion peptide occupied a leaflet of the DMPC bilayer, the opposite leaflet invaginated with influx of water and choline headgroups in around Asp830 and bilayer-inserted polar sidechains. NMR-detected hydrogen exchange found corroborating hydration of the backbone of Thr827 – Phe833 inserted deeply in bicelles. Pinching of the membrane at the inserted charge and the intramembrane hydration of polar groups agree with theory. Formation of corridors of hydrated, inward-turned headgroups was accompanied by flip-flop of headgroups. Potential roles of the defects are discussed.
Keywords
viral-cell fusion, charge insertion in membrane, membrane electrostriction, intramembrane hydration, fusion peptide, lipid flip-flop, lipid tail protrusion, lipid headgroup intrusion, membrane thinning, fusogenic subunit, NMR-biased molecular dynamics, paramagnetic relaxation enhancements
