Abstract
To gain insight into the atomistic details of membrane fusion induced by fusogenic peptides, molecular dynamic simulations of synthetic peptides, derived from viral fusion proteins, contained in lipid bilayers were performed. A 20 amino acid peptide from the N-terminus of the influenza HA fusion peptide (WT20) assumed the oblique orientation at the interface between water and the membrane made up of dipalmitoylphosphatidylcholine (DPPC)/palmitic acid (PA), as reported previously for different membranes. Simulations of WT20 embedded in bilayer membranes made up of dioleoylphos-phatidylethanolamine (DOPE) and DPPC/PA showed a positive curvature-inducing effect, whereas WT20 showed a negative curvature-inducing effect on a DPPC bilayer. In phase re-constitution analyses starting from a random mixture of DPPC, PA and water molecules, WT20 weakly stabilized an inverted hexagonal phase. In the latter analyses WT20 preferentially assumed a transmembrane orientation as opposed to the interfacial orientation, regardless of the phase to which the system settled (lamellar vs. inverted hexagonal). In another set of analyses using systems containing a water layer between the apposed DPPC/PA (and DOPE) monolayers, the behavior of WT20 during the formation of an intermembrane connection (or stalk) was examined. Comparison among the mutants supports a view that the oblique orientation of WT20 facilitates the perturbation of the lipid-water interface and the stalk formation. Taken together, these results imply that the influenza HA fusion peptide can have substantial effects on the membrane curvature and can assume a wide range of orientation/position in membranes depending on the local environment of the lipid/water system. Its movability and oblique orientation appear to be associated with its ability to perturb membrane/water interfaces.
Highlights
Fusion of viral and plasma or endosomal membranes is mediated by envelope glycoproteins, known as fusion proteins
Does WT20 alter the membrane curvature? Experiments using dipalmitoleoylphosphatidylethanolamine (DiDOPE) by Epand and Epand [63] have shown that the wildtype peptide lowers the temperature of the phase transition from bilayer to hexagonal at pH 5 while it raises the temperature at pH 7.4
The difference in lipid composition makes it difficult to compare the experimental findings with our results, our findings suggest a possibility that molecular dynamics (MD) simulations can complement experimental phase analyses in the presence of peptides
Summary
Fusion of viral and plasma or endosomal membranes is mediated by envelope glycoproteins, known as fusion proteins. Tamm and coworkers, using NMR and EPR, showed that the FP of HA (or HAFP) forms a shallow-angle inverted V structure [31,32] Their subsequent studies of the mutants G1V and W14A support the view that the inverted V shape and/or oblique orientation plays an important role in the fusogenicity of the peptide [33,34]. A recent study on oligomerization of HAFP, which utilized an implicit treatment of water, has shown that many different configurations (peptide/peptide and peptide/membrane) have similar energy levels [49] How such structural features of FPs are associated with its fusogenicity is important. Given the previous simulation studies of HAFP with the DMPC and POPC membranes [46,47,48], we here attempted to examine the peptide dynamics in lipid structures involving non-lamellar ones. Since this approach cannot stand alone, experimental and structural studies that solidify the hypothesis are necessary
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