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Review
. 2021 Dec;11(12):3253-3261.
doi: 10.1002/2211-5463.13323. Epub 2021 Nov 8.

Molecular mechanisms of the influenza fusion peptide: insights from experimental and simulation studies

Diana Lousa  1 , Cláudio M Soares  1
Affiliations
Review

Molecular mechanisms of the influenza fusion peptide: insights from experimental and simulation studies

Diana Lousa et al. FEBS Open Bio. 2021 Dec.

Abstract

A key step in infections by enveloped viruses, such as influenza, is the fusion between the viral envelope and the host cell membrane, which allows the virus to insert its genetic material into the host cell and replicate. The influenza virus fusion process is promoted by hemagglutinin (HA), a glycoprotein that contains three identical monomers composed of two polypeptide chains (HA1 and HA2). Early studies on this protein revealed that HA-mediated fusion involves the insertion of the HA2 N-terminal segment into the host membrane and that this segment, known as the fusion peptide, is a key player in the fusion process. This mini-review highlights the main findings that have been obtained by experimental and computational studies on the HA fusion peptide, which give us a glimpse of its mode of action.

Keywords: biophysical assays; hemagglutinin; influenza; membrane fusion; molecular dynamics simulation; virus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1
General mechanism of membrane fusion catalyzed by hemagglutinin. The scheme shows the sequence of events that occur during the fusion process. (A) Initially, the protein is in a prefusion conformation. (B) A pH decrease promotes large conformational changes, leading to the formation of an extended intermediate, which enables the insertion of the FP (shown in red) in the host membrane. (C) The protein folds back, zipping up the outer regions against the inner core and pushing the host membrane toward the viral membrane. (D) The two membranes come into contact, forming a hemifusion stalk. (E) The formation of a pore completes the fusion process. Adapted from ref. [3].
Fig. 2
Fig. 2
NMR structures of the IFP in detergent micelles. (A) Structure of a synthetic peptide composed by the first 20‐aa residues of HA2 (strain X:31), obtained at pH 7.4 in DPC micelles, determined by 1H‐NMR (PDB ID: 1IBN [25]). (B) Structure of the same peptide described in (A), at pH 5 (PDB ID: 1IBO [25]). (C) Structure of a synthetic peptide composed by the first 23‐aa residues of HA2 (from the H1 sero‐subtype) obtained at pH 7.4 in DPC micelles, determined by 1H‐NMR (PDB ID: 2KXA [26]). The structure of the same peptide at pH 4 does not have considerable structural changes relative to the structure at pH 7.4. The figures were built with pymol [67], using a cartoon representation for the peptide backbone with carbons colored in gold in the 20‐residue long peptide and in teal in the 23‐residue long peptide.
Fig. 3
Fig. 3
Conformations adopted by the IFP and their effect in the membrane. The conformations were obtained in constant‐pH MD simulations [66] starting from two distinct conformations (labeled as horizontal and vertical) obtained using a self‐assembly approach [37]. (A) Illustration of a lipid tail protrusion event promoted by interaction of a lipid with the peptide N terminus, observed in the constant‐pH MD simulations performed at pH 5 starting from the horizontal conformation [66] (this snapshot corresponds to the 114th ns of replicate 4). (B) Illustration of a lipid tail protrusion event promoted by interaction of a lipid with the peptide N terminus, observed in the constant‐pH MD simulations performed at pH 5 starting from the vertical conformation [66] (this snapshot corresponds to the 597th ns of replicate 4). The images were built with pymol [67]. The IFP is shown using a cartoon representation colored in teal, the lipid phosphorus atoms are depicted by orange spheres and the N terminus of G1, as well as the side chains of E11, W14, and D19 are highlighted using sticks.
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