Abstract
The conserved N-terminal residues of the HA2 subunit of influenza hemagglutinin (fusion peptide) are essential for membrane fusion and viral entry. Recent NMR studies showed that the 23-residue fusion peptide forms a helical hairpin that undergoes rocking motion relative to the membrane surface on a nanosecond time scale. To compare with NMR and to obtain a detailed molecular picture of the peptide-membrane interaction, we performed molecular dynamics simulations of the fusion peptide in explicit dimyristoylphosphatidylcholine and with the IMM1 implicit membrane model. To account for low and neutral pH conditions, simulations were performed with acidic groups (E11 and D19) protonated and unprotonated, respectively. The hairpin structure was stable in the simulations, with the N-terminal helix buried more deeply into the hydrophobic membrane interior than the C-terminal helix. Interactions between the tryptophans in the fusion peptide and phospholipid residues contribute to peptide orientation. Higher flexibility of the hairpin was observed in the implicit membrane simulations. Internal correlation functions of backbone N-H vectors were fit to the extended Lipari-Szabo model-free approach to obtain order parameters and correlation times. Good agreement with the NMR results was obtained for orientational fluctuations around the hairpin axis (rotation), but those around the perpendicular axis (tilting) were more limited in the simulations than inferred from the NMR experiments.