Lipid Tail Protrusion in Simulations Predicts Fusogenic Activity of Influenza Fusion Peptide Mutants and Conformational Models

Membrane fusion is a common process critical to both cellular function and infection by enveloped viruses. Influenza is a particularly useful model system for studying fusion because the fusion reaction is accomplished by a single protein, hemagglutinin. Furthermore, mutations to the membrane-inserted portion of hemagglutinin have been identified that do not detectably alter the rest of the protein but can either arrest fusion halfway or block it entirely. For influenza at least, it seems that the membrane-inserted hemagglutinin peptide plays a critical role in promoting fusion, perhaps by increasing the local disorder of lipid bilayers. However, we lack a mechanistic understanding sufficient to predict the activity of fusion peptide mutants from their sequence. Here, we have used lipid tail protrusion as a way to measure how much fusion peptides disorder their surrounding bilayer; we see a strong relationship between lipid tail protrusion and the ability of fusion peptide mutants to promote lipid mixing between membranes. Our simulations also predict that this lipid tail protrusion is much more common when the peptides adopt a kinked helix structure than when they are straight or hairpin-like. We therefore hypothesize that, while all three types of structure likely undergo conformational exchange, the kinked helix structure is most active in promoting fusion.