Lipid Tail Protrusion could Explain Fusogenic Activity in Influenza Hemaggluttinin

Abstract

Influenza is both a major human pathogen and a common model system for studying viral entry mechanisms. One outstanding question in influenza viral entry has been the role of the membrane-inserted hemagglutinin fusion peptide. Point mutations to the fusion peptide can either block fusion entirely, as in the N-terminal glycine mutant (G1V), or cause arrest at hemifusion, as in the G1S mutant. Recently, we and others have proposed that fusion stalks are nucleated by contact of protruding acyl tails. In simulations, we have shown that native influenza fusion peptides promote this tail protrusion.Here, we have performed a series of simulations with wild-type fusion peptide as well as G1V and G1S mutants. Lipid tail protrusion close to the fusion peptides correlates well with experimental fusion activity, being increased for the wild-type structure over the G1V mutant, with G1S as an intermediate. This suggests that tail protrusion may indeed be a good marker for fusion and an important first step in the fusion process.Our simulations also examine the role that peptide structure may play in promoting fusion. We predict that the three main structural models for the fusion peptide may interconvert based on relatively minor changes to their environment. Using lipid tail protrusion as a surrogate metric, we predict the kinked helix model to have much greater fusion activity than either the helical hairpin or the flat helix.