Abstract

Fusion peptides from influenza hemagglutinin act on membranes to promote membrane fusion, but the mechanism by which they do so remains unknown. Recent theoretical work has suggested that contact of protruding lipid tails may be an important feature of the transition state for membrane fusion. If this is so, then influenza fusion peptides would be expected to promote tail protrusion in proportion to the ability of the corresponding full-length hemagglutinin to drive lipid mixing in fusion assays. We have performed molecular dynamics simulations of influenza fusion peptides in lipid bilayers, comparing the X-31 influenza strain against a series of N-terminal mutants. As hypothesized, the probability of lipid tail protrusion correlates well with the lipid mixing rate induced by each mutant. This supports the conclusion that tail protrusion is important to the transition state for fusion. Furthermore, it suggests that tail protrusion can be used to examine how fusion peptides might interact with membranes to promote fusion. Previous models for native influenza fusion peptide structure in membranes include a kinked helix, a straight helix, and a helical hairpin. Our simulations visit each of these conformations. Thus, the free energy differences between each are likely low enough that specifics of the membrane environment and peptide construct may be sufficient to modulate the equilibrium between them. However, the kinked helix promotes lipid tail protrusion in our simulations much more strongly than the other two structures. We therefore predict that the kinked helix is the most fusogenic of these three conformations.

Highlights

  • Membrane fusion is critical to eukaryotic cellular function and provides the mode of entry for enveloped viruses such as influenza and HIV

  • 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 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

Read more

Summary

Introduction

Influenza viral entry is mediated by the hemagglutinin protein As part of this process, short fusion peptides are inserted into the host membrane and act to promote fusion. Influenza is a distinctive system for studying fusion because hemagglutinin mutants have been generated that can insert fusion peptides and pull viral and target membranes together but not complete the fusion process [1,2,3,4,5]. This can be accomplished via mutations in the fusion peptide region or deletions in the transmembrane domain. The mechanism by which fusion peptides act on membranes remains unknown, but some possibilities that have been previously suggested include inducing membrane curvature, altering local membrane composition, and inducing local disorder in membrane lipids [6,7,8,9]

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call