Binding of SARS-CoV-2 fusion peptides to hybrid phospholipid bilayers: exploring the influence of ether-linked...

Ether phospholipids are believed to play crucial roles in various biological functions. Previous research has indicated that substituting ester linkages with ether linkages in lipid head groups leads to a significant reduction in the membrane dipole potential. In this study, we constructed hybrid lipid bilayer systems that included both ether-linked (DMPCE) and ester-linked (DMPC) phospholipids. Our goal was to understand how the ether lipid content in the hybrid lipid bilayers affects the interaction between the SARS-CoV-2 fusion peptide (FP) and cellular membranes. To achieve this, we systematically adjusted the stoichiometric ratios to create four hybrid membrane models: two were ester-predominant and another two were ether-enriched. Our molecular dynamics (MD) simulations revealed several intriguing findings. First, it is surprising that at low-to-moderate DMPCE concentrations, the presence of ether phospholipids caused only minor changes in the overall structural properties of the hybrid bilayer membranes, including the membrane dipole potential. However, at a higher level of ether lipid, there is a significant impact on the structural properties and the dipole potential of the lipid bilayer membrane. This composition-dependent behavior implies that while the structural integrity of ester lipid bilayers remains relatively unaffected by low-to-moderate levels of ether lipid incorporation, exceeding a critical concentration threshold would result in observable structural changes in the lipid bilayer. Furthermore, the content of ether phospholipids had a significant impact on the conformation of the SARS-CoV-2 FP and its binding to hybrid membranes. Our current results indicate that the biophysical effects of partial ether lipid substitution follow a non-linear response to composition. This refined understanding advances earlier models by demonstrating that hybrid bilayers maintain compositional resilience within specific operational ranges.