The role of N-terminal acetylation of COVID fusion peptides in the interactions with liquid-ordered lipid bilayers

The partitioning of viral fusion peptides in lipid membranes with varying order was investigated due to the fusion mechanism being a potential therapeutic approach. Using a planar bilayer model and advanced techniques such as neutron reflectometry (NR) and quartz crystal microbalance with dissipation (QCM-D), the structural aspects of peptide-lipid interactions were explored. The study focused on two target membranes: one forming a liquid-ordered domain and the other forming a liquid-disordered domain. Surprisingly, the COVID fusion peptide did not bind significantly to either membrane, as demonstrated by both QCM-D and NR data, suggesting negligible or no interaction with the bilayers. However, the acetylated COVID fusion peptide showed distinct behaviour, indicating a crucial role of N-terminal acetylation in binding to cholesterol-rich liquid-ordered domains. The acetylated peptide induced changes in the structure and thickness of the ordered bilayer with cholesterol whereas proteins and peptides commonly only bind to disordered phases. This study provides valuable insights into the mechanisms of viral membrane fusion and highlights the importance of acetylation in influencing peptide-lipid interactions, laying the groundwork for potential antiviral therapeutic strategies.