Aspects of the Fusogenic Activity of Influenza Hemagglutinin Peptides by Molecular Dynamics Simulations

Abstract

The interactions of the fusion domain of influenza hemagglutinin (HA) (N-terminal 20 residues, the fusion peptide) with a POPC lipid bilayer have been studied by molecular dynamics (MD) simulations. This domain is considered a model system for studying processes occurring during viral membrane fusion. Synthetic peptides corresponding to this domain are able to cause red blood cell hemolysis and leakage of liposomal content. Mutations in their sequences lead to homologs with fusion properties similar to whole HA molecules with the corresponding sequence changes. Detailed information about the molecular interactions leading to insertion into the core of the lipid bilayer can be obtained by the analysis of our simulations. We observe that the N-terminal 11 residues of the fusion peptides are helical and insert with a tilt angle with respect to the membrane plane of about 30°, in very good agreement with experimental data. The tilt angle stabilizes around the final value only after 4 ns. Residues Glu11, Glu15, and Asp19 are positioned at the level of the lipid phosphate groups, and the last peptide segment can either be helical or unfolded without altering dramatically the tilting of the first N-terminal 11 residues. The membrane bilayer experiences a thinning caused by the presence of the peptides and the calculated order parameters show larger disorder of the alkyl chains. These results indicate a perturbed lipid packing upon peptide insertion that could facilitate membrane fusion.