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

The "fusion peptide," a segment of similar to 20 residues of the influenza hemagglutinin (HA), is necessary and sufficient for HA-induced membrane fus ion. We used mean-field calculations of the free energy of peptide-membrane association (DeltaG(tot)) to deduce the most probable orientation of the f usion peptide in the membrane. The main contributions to DeltaG(tot) are pr obably from the electrostatic (DeltaG(el)) and nonpolar (DeltaG(np)) compon ents of the solvation free energy; these were calculated using continuum so lvent models. The peptide was described in atomic detail and was modeled as an a-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 DeltaG(tot) tha n 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 p lane, its hydrophobic face dissolved in the bilayer, and its polar face in the water. The associated DeltaG(tot) value was similar to -8 to -10 kcal/m ol (depending on the rotameric state of one of the phenylalanine residues). In contrast, the DeltaG(tot) values associated with experimentally observe d oblique orientations were found to be near zero, suggesting they are marg inally stable at best. The theoretical model did not take into account the interactions of the polar headgroups with the peptide and peptide-induced m embrane deformation effects. Either or both may overcompensate for the Delt aG(tot) difference between the horizontal and oblique orientations.