Condensation of the influenza viral fusion peptide alters membrane structure and water permeability

Abstract To infect, enveloped viruses employ spike protein, spearheaded by its amphipathic fusion peptide (FP), that upon activation extends out beyond a forest of viral spikes to embed into the target cellular membrane. Here we report that isolated FP of influenza virus are membrane active by themselves generating pores in giant unilamellar vesicles and thus potentially explain both influenza virus’ hemolytic activity and structure in cryo-electron tomography. Molecular dynamics simulations of asymmetric bilayers with different numbers of FP in one leaflet show substantial peptide clustering. At the center of this peptide condensate a profound change in the membrane structure results in thinning, higher water permeability, and curvature. In effect, a hybrid bilayer forms locally with one lipid monolayer and one peptide monolayer. Membrane elastic theory predicts that the energy landscape becomes favorable for spontaneous pore formation in this novel structure, consistent with the inhibition of pore formation by cholesterol observed experimentally.