Bilayer Conformation of Fusion Peptide of Influenza Virus Hemagglutinin: A Molecular Dynamics Simulation Study

Abstract

Unraveling the conformation of membrane-bound viral fusion peptides is essential for understanding how those peptides destabilize the bilayer topology of lipids that is important for virus-cell membrane fusion. Here, molecular dynamics (MD) simulations were performed to investigate the conformation of the 20 amino acids long fusion peptide of influenza hemagglutinin of strain X31 bound to a dimyristoyl phosphatidylcholine (DMPC) bilayer. The simulations revealed that the peptide adopts a kinked conformation, in agreement with the NMR structures of a related peptide in detergent micelles. The peptide is located at the amphipathic interface between the headgroups and hydrocarbon chains of the lipid by an energetically favorable arrangement: The hydrophobic side chains of the peptides are embedded into the hydrophobic region and the hydrophilic side chains are in the headgroup region. The N-terminus of the peptide is localized close to the amphipathic interface. The molecular dynamics simulations also revealed that the peptide affects the surrounding bilayer structure. The average hydrophobic thickness of the lipid phase close to the N-terminus is reduced in comparison with the average hydrophobic thickness of a pure dimyristoyl phosphatidylcholine bilayer.

The influenza fusion peptide promotes lipid polar head intrusion through hydrogen bonding with phosphates and N-terminal membrane insertion depth

“…S8). This result is consistent with a thinning of the membrane induced by the peptide, as reported by many previous studies …”

“…The molecular mechanism by which FPs promote lipid mixing between two juxtaposed membranes remains to be elucidated. Although many FP‐induced membrane perturbations associated with fusion have been proposed such as membrane thinning, membrane curvature, changes in lipid order, and lipid tilting, they are insufficient to generate a comprehensive molecular model for lipid mixing catalysis. It is indeed not clear how these perturbations can establish a localized hydrophobic contact between bilayers to initiate stalk formation .…”

Lipid Tail Protrusion in Simulations Predicts Fusogenic Activity of Influenza Fusion Peptide Mutants and Conformational Models

“…NMR experiments in micelles and EPR experiments in bilayers have provided a kinked helix model for the structure of the fusion peptide of X-31 (H3) hemagglutinin in bilayers. This model is consistent with additional infrared and circular dichroism spectroscopic data [6], [14], [15]. Solid-state NMR experiments in bilayers have yielded structures that are grossly similar but have a slightly more pronounced kink [16].…”

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.…”