Pathway of pore formation by influenza fusion peptides investigated in atomistic detail.

Abstract

The fusion peptide (FP) domain is responsible for the fusogenic activity of spike glycoproteins in a variety of enveloped viruses. As the only portion of the protein that interacts directly with the target membrane lipid tails, this domain is integral to the virus’ ability to infect the host cell. Additionally, experiments have consistently demonstrated the ability of the fusion peptide domain to porate or rupture model membrane systems. Here, we present the results of over 120 μs of atomistic molecular dynamics simulations investigating the pathway by which FP-induced pores form in membranes composed of lysolipid and POPC. Both isolated FP and FP aggregates spontaneously form pores in these membranes on hundred-ns time scales. Pores formed by isolated FP are generated in the lipid portion of the membrane, rather than under the peptide, consistent with the classical view of peptides as membrane components that alter the average properties of the leaflet. Peptide aggregates, on the other hand, mostly form pores via peptide-pore intermediates, where the cis leaflet is spanned primarily by highly tilted FP, locally reducing the hydrophobic thickness that must be bridged by a water wire or hydrophobic defect. By restraining a single FP within an FP aggregate to this tilted conformation, pores form in lower lysolipid-content membranes, including pure POPC, through a similar pathway.