Viral entry mechanisms: the role of molecular simulation in unlocking a key step in viral infections

Abstract

Viral infections are a major global health concern, affecting millions of people each year. Viral entry is one of the crucial stages in the infection process, but its details remain elusive. Enveloped viruses are enclosed by a lipid membrane that protects their genetic material and these viruses are linked to various human illnesses, including influenza, and COVID-19. Due to the advancements made in the field of molecular simulation, significant progress has been made in unraveling the dynamic processes involved in viral entry of enveloped viruses. Simulation studies have provided deep insight into the function of the proteins responsible for attaching to the host receptors and promoting membrane fusion (fusion proteins), deciphering interactions between these proteins and receptors, and shedding light on the functional significance of key regions, such as the fusion peptide. These studies have already significantly contributed to our understanding of this critical aspect of viral infection and assisted the development of effective strategies to combat viral diseases and improve global health. This review focuses on the vital role of fusion proteins in facilitating the entry process of enveloped viruses and highlights the contributions of molecular simulation studies to uncover the molecular details underlying their mechanisms of action.

Keywords: enveloped viruses; fusion peptide; membrane fusion; molecular simulation; receptor binding; viral entry.

Fig. 1

Generic illustration of the successive stages facilitated by viral fusion proteins to enable viral fusion. This depiction highlights the pivotal role of fusion proteins in this process and the conformational alterations they experienced throughout the fusion event. Experimental and computational methodologies can be utilized to describe each phase of this process, which are shown at the bottom of the figure.

Fig. 2

(A) Antibody contact map represented on the spike protein surface, seen from front (left side) and from top (right side); the map was built with VMD [138] and the color gradient is used to represent the log of the frequency of contact with Ab as shown in the scale bar. Reproduced with permission from Ref. [54]. Copyright © 2021 Public Library of Science. (B) Molecular representation of the glycan shield of the SARS‐CoV‐2 S protein in the “up” state. Glycans at several frames (namely, 300 frames, one every 30 ns from one replica) are represented with blue lines, the protein is shown with cartoons and highlighted with a cyan transparent surface. Adapted with permission from Ref. [90]. Copyright © 2020 American Chemical Society. (C) Representation of the “open”, “closed” and “reversed” conformations of the SARS‐CoV‐2 RBD seen by molecular dynamics simulations.

Fig. 3

(A) Pre‐fusion crystal structures of the PIV5 F protein in the uncleaved (green) [15] and cleaved (red) [139] states. Figures (A) and (B) were reprinted with permission from [97]. Copyright © 2014 American Chemical Society. (B) PIFP structure determined by SS‐NMR in POPC/POPG and DOPC/DOPG bilayers. The peptide is fully α‐helical in POPC/POPG bilayers, but adopts a mixed strand/helix conformation in DOPC/DOPG bilayers [97]. (C) Snapshot of PIFP hexameric bundle obtained from a short MD simulation (50 ns). The Q120 residues form hydrogen bonds with one another as well as with waters on the interior. Waters are shown in blue, highlighting the penetration of water into the core of the 6HB from the viral side of the membrane. Reprinted with permission from [98]. Copyright © 2011 National Academy of Sciences.

Fig. 4

(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 vertical conformation. Reprinted with permission from [140]. Copyright © 2021 FEBS Press. (B) Illustration of 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. (C) Snapshot of the six PIFPs inserted in the membrane, where a lipid is highlighted in blue to evidence the lipid tail protrusion event. (D) Snapshot of the nine PIFPs inserted in the membrane, the water crossing the pore‐like structure formed by the peptides are highlighted. Figures (C) and (D) were reprinted with permission from [119]. Copyright © 2022 American Chemical Society.

Fig. 5

(A) Atomic‐resolution simulations of a small proteoliposome docked to a planar bilayer by three full‐length hemagglutinin trimers resulted in fusion stalk formation, and finally a nascent fusion pore (from left to right). Adapted with permission from [133]. Copyright © 2020 Proceedings of the National Academy of Sciences. (B) Model of the SARS‐CoV‐2 spike protein pre‐ to post‐fusion transition. Following the dissociation of S2 from S1, the unstructured pre‐fusion HR1 loops become helical (loaded spring release), giving the HR1‐CH backbone that thrusts the FPs toward the host cell membrane. The FI subsequently refolds into the post‐fusion structure. Adapted with permission from [135]. Copyright © 2023 American Chemical Society.