Molecular Dynamics Simulations of Influenza Fusion Peptide: A Correlation between Flexibility and Fusogenicity

Abstract

A flu infection starts with the entry of the influenza virus into an host cell. Entry requires endocytosis of the virus by the host cell and subsequent fusion between the viral and endosomal phospholipid membranes. This important membrane fusion step is catalysed by the influenza fusion peptide whose action mode remains unsung. Detailed knowledge on the fusion peptide is essential for the development of therapeutics as well as to understand many biological processes since membrane fusion is ubiquitous to life.Previous experiments on fusion peptides from various influenza strains and their respective mutants aimed to unveil a structure-function relationship without general agreement. The peptides were shown to adopt a helix-hinge-helix motif essential for fusogenicity, but results diverged on the hinge region which strongly impacts on the peptide structure. The hinge region was sometimes shown as flexible (Dubovskii, Prot. Science 9:786), as a fixed kink (Han, Nat. Struc. Biol. 8:715) or as a tight hairpin (Lorieau, PNAS 107:11341). Similar disagreement occurred in modelling studies (Jang, Proteins 72:299 ; Li, J. Phys. Chem. B 114:8799 ; Panahi, J. Phys. Chem. B 114:1407).In this work, the structure-function relationship of the fusion peptide from type three hemagglutinin and two mutants (F9A and W14A) were studied from extensive explicit solvent molecular dynamics simulations. Our results show that the hinge region of the fusion peptide is flexible and allows it to be in an equilibrium between kinked and helical conformations. The two mutants also show a different flexibility than the wild-type. Moreover, a correlation between peptide flexibility, lipid protrusion (proposed as the membrane fusion catalysis mechanism (Kasson, PLoS Comput. Biol. 6:e1000829)) and fusogenicity reported in the literature was observed.