Abstract
Hemagglutinin (HA) mediated fusion of influenza virus envelope with host lipid membrane is a critical step warrantying virus entry to the cell. Despite tremendous advances in structural biology methods, the knowledge concerning the details of HA2 subunit insertion into the target membrane and its subsequent bilayer perturbing effect is still rather limited. Herein, based on a set of molecular dynamics simulations, we investigate the structure and interaction with lipid membrane of the N-terminal HA2 region comprising a trimer of fusion peptides (HAfps) tethered by flexible linkers to a fragment of coiled-coil stem structure. We find that, prior to insertion into the membrane, HAfps within the trimers do not sample space individually but rather associate into a compact hydrophobic aggregate. Once within the membrane, they fold into tight helical hairpins, which remain at the lipid-water interface. However, they can also assume stable, membrane-spanning configurations of significantly increased membrane-perturbing potential. In this latter case, HAfps trimers centre around the well-hydrated transmembrane channel-forming distinct, symmetric assemblies, whose wedge-like shape may play a role in promoting membrane curvature. We also demonstrate that, following HAfps insertion, the coiled-coil stem spontaneously tilts to almost membrane-parallel orientation, reflecting experimentally observed configuration adopted in the course of membrane fusion by complete HA2 units at the rim of membrane contact zones.
Highlights
Influenza is a respiratory system disease that humanity has been facing since ancient times (Potter and Jennings, 2011; Lipsitch et al, 2016)
In its fusion-active configuration, the trimeric HA2 subunit adopts a form of an extended 15 nm long rod, which is anchored in the viral membrane via C-terminal transmembrane domains (TMDs) (Benton et al, 2020)
In this work, based on a series of molecular dynamics (MD) simulations, we analysed in atomistic detail the geometry and membrane-perturbing potential of the trimeric HA2 fusogenic region
Summary
Influenza is a respiratory system disease that humanity has been facing since ancient times (Potter and Jennings, 2011; Lipsitch et al, 2016). Once the virus is encapsulated inside an endosome and exposed to its low internal pH, it undergoes partial refolding, resulting in the Membrane Binding of Influenza HA2 N-Terminus formation of an extended coiled-coil stem directed towards the endosomal membrane (Benton et al, 2020) This rigid, elongated structure is capped with flexible N-terminal HA2 regions, known as fusion peptides (HAfps), which insert into the host membrane and are directly responsible for its subsequent merger with the viral lipid envelope (Nieva and Agirre, 2003; Vaccaro et al, 2005; White et al, 2008; Apellániz et al, 2014). There are many well-characterised point mutations that arrest or completely abrogate the fusion process in spite of preserved peptides’ ability to associate with the lipid bilayer (Steinhauer et al, 1995; Langley et al, 2009)
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