Single mutation effects on conformational change and membrane deformation of influenza hemagglutinin fusion peptides.

The single mutation effect on the conformational change and membrane permeation of influenza hemagglutinin fusion peptides has been studied with molecular dynamics simulations. A total of seven peptides, including wild-type fusion peptide and its six single point mutants (G1E, G1S, G1V, G4V, E11A, and W14A, all with no fusion or hemifusion activity) are examined systematically, which covers a wide range of mutation sites as well as mutant residue types (both hydrophobic and hydrophilic). The wild-type shows a kink structure (inversed V-shape), which facilitates the interaction between the fusion peptide and the lipid bilayer, as well as the interaction between the two arms of the fusion peptide. All mutants show a strong tendency toward a linear alpha-helix conformation, with the initial kink structure in the wild-type broken. More interestingly, one of the key hydrophobic residues around the initial kink region, Phe-9, is found to flip away from the membrane surface in most of these mutants. This conformational change causes a loss of key interactions between the original two arms of the inversed V-shape of the wild-type, thus disabling the kink structure, which results in the stabilization of the linear alpha-helix structure. The fusion peptides also display significant impact on the membrane structure deformation. The thickness of the lipid bilayer surrounding the wild-type fusion peptide decreases significantly, which induces a positive curvature of lipid bilayer. All the single mutations examined here reduce this membrane structural deformation, supporting the fusion activity data from experiments.