Implicit solvent model studies of the interactions of the influenza hemagglutinin fusion peptide with lipid bilayers

The "fusion peptide," a segment of ∼20 residues of the influenza hemagglutinin (HA), is necessary and sufficient for HA-induced membrane fusion. We used mean-field calculations of the free energy of peptide-membrane association (ΔG_tot) to deduce the most probable orientation of the fusion peptide in the membrane. The main contributions to ΔG_tot are probably from the electrostatic (ΔG_el) and nonpolar (ΔG_np) components of the solvation free energy; these were calculated using continuum solvent models. The peptide was described in atomic detail and was modeled as an α-helix based on spectroscopic data. The membrane's hydrocarbon region was described as a structureless slab of nonpolar medium embedded in water. All the helix-membrane configurations, which were lower in ΔG_tot than the isolated helix in the aqueous phase, were in the same (wide) basin in configurational space. In each, the helix was horizontally adsorbed at the water-bilayer interface with its principal axis parallel to the membrane plane, its hydrophobic face dissolved in the bilayer, and its polar face in the water. The associated ΔG_tot value was ∼-8 to -10 kcal/mol (depending on the rotameric state of one of the phenylalanine residues). In contrast, the ΔG_tot values associated with experimentally observed oblique orientations were found to be near zero, suggesting they are marginally stable at best. The theoretical model did not take into account the interactions of the polar headgroups with the peptide and peptide-induced membrane deformation effects. Either or both may overcompensate for the ΔG_tot difference between the horizontal and oblique orientations.