 Lipid Tail Protrusion in Simulations Predicts Fusogenic Activity of Influenza Fusion Peptide Mutants and Conformational ModelsPer Larsson and Peter M Kasson PLOS Computational Biology, 2013, vol. 9, issue 3, 1-9 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. Author Summary: 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. Date: 2013 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1002950 DOI: 10.1371/journal.pcbi.1002950 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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