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

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.