Plasticity of Influenza Haemagglutinin Fusion Peptides and Their Interaction with Lipid Bilayers

Abstract

A detailed molecular dynamics study of the haemagglutinin fusion peptide (N-terminal 20 residues of the HA2 subunits) in a model bilayer has yielded useful information about the molecular interactions leading to insertion into the lipids. Simulations were performed on the native sequence, as well as a number of mutant sequences, which are either fusogenic or nonfusogenic. For the native sequence and fusogenic mutants, the N-terminal 11 residues of the fusion peptides are helical and insert with a tilt angle of approximately 30 degrees with respect to the membrane normal, in very good agreement with experimental data. The tilted insertion of the native sequence peptide leads to membrane bilayer thinning and the calculated order parameters show larger disorder of the alkyl chains. These results indicate that the lipid packing is perturbed by the fusion peptide and could be used to explain membrane fusion. For the nonfusogenic sequences investigated, it was found that most of them equilibrate parallel to the interface plane and do not adopt a tilted conformation. The presence of a charged residue at the beginning of the sequence (G1E mutant) resulted in a more difficult case, and the outcomes do not fall straightforwardly into the general picture. Sequence searches have revealed similarities of the fusion peptide of influenza haemagglutinin with peptide sequences such as segments of porin, amyloid alpha eta peptide, and a peptide from the prion sequence. These results confirm that the sequence can adopt different folds in different environments. The plasticity and the conformational dependence on the local environment could be used to better understand the function of fusion peptides.

Autocatalytic Activation of Influenza Hemagglutinin

“…Insertion of exposed fusion peptides into the cell membrane (or N-terminal 11 residues of the fusion peptide in the HA3.1 mutant) could alter membrane tension and curvature with resulting effects on trimer conformational stability; membrane tension has been observed to impact folded stability of bacterial outer membrane protein A. 25 This supposition is also consistent with the suggested structure of membrane-embedded HA fusion peptide, [26][27][28][29] in which the N-terminal portion of the fusion peptide embeds into the non-polar membrane core and disrupts lipid structure. However, despite the observed thermolysin sensitivity of the autocatalytic refolding, direct evidence for membrane involvement in this phenomenon and for the existence of autocatalytic HA refolding in the context of intermembrane fusion requires further studies.…”

Molecular Dynamics Simulations of the Influenza Hemagglutinin Fusion Peptide in Micelles and Bilayers: Conformational Analysis of Peptide and Lipids

“…13 Recent molecular dynamics (MD) simulations of the fusion peptide in bilayers 14,15 support these ideas; i.e. the peptide, located at the lipid/water interface, has two helices separated by a kink, and induces the thinning of the membrane 14,15 and lowers the lipid chain order parameters. 14 Despite these advances, numerous issues remain unresolved.…”

“…the peptide, located at the lipid/water interface, has two helices separated by a kink, and induces the thinning of the membrane 14,15 and lowers the lipid chain order parameters. 14 Despite these advances, numerous issues remain unresolved. First, although there are indications that the fusion peptide has roughly the same secondary structure in micelles and bilayers, 6,10 subtle and potentially important differences may occur.…”

HA2 glycopolypeptide of influenza A virus and antiviral immunity

“…The conformation change is temperature-dependent, i.e. an increased temperature accelerates the HA refolding (Yewdell et al, 1983;Skehel and Wiley, 2000;Vaccaro et al, 2005). The low pH-change of HA is irreversible and is accompanied by modified antigenic properties (Daniels et al, 1983;Yewdell et al, 1983;Webster et al, 1983).…”