Binding of SARS-CoV-2 Fusion Peptide to Host Endosome and Plasma Membrane.
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TLDR
In this paper, the SARS-CoV-2 virus fuses its viral envelope with cellular membranes of its human host and forms an anchor strong enough to withstand the mechanical force during membrane fusion.Abstract:
During infection the SARS-CoV-2 virus fuses its viral envelope with cellular membranes of its human host. The viral spike (S) protein mediates both the initial contact with the host cell and the subsequent membrane fusion. Proteolytic cleavage of S at the S2' site exposes its fusion peptide (FP) as the new N-terminus. By binding to the host membrane, the FP anchors the virus to the host cell. The reorganization of S2 between virus and host then pulls the two membranes together. Here we use molecular dynamics (MD) simulations to study the two core functions of the SARS-CoV-2 FP: to attach quickly to cellular membranes and to form an anchor strong enough to withstand the mechanical force during membrane fusion. In eight 10 μs long MD simulations of FP in proximity to endosomal and plasma membranes, we find that FP binds spontaneously to the membranes and that binding proceeds predominantly by insertion of two short amphipathic helices into the membrane interface. Connected via a flexible linker, the two helices can bind the membrane independently, yet binding of one promotes the binding of the other by tethering it close to the target membrane. By simulating mechanical pulling forces acting on the C-terminus of the FP, we then show that the bound FP can bear forces up to 250 pN before detaching from the membrane. This detachment force is more than 10-fold higher than an estimate of the force required to pull host and viral membranes together for fusion. We identify a fully conserved disulfide bridge in the FP as a major factor for the high mechanical stability of the FP membrane anchor. We conclude, first, that the sequential binding of two short amphipathic helices allows the SARS-CoV-2 FP to insert quickly into the target membrane, before the virion is swept away after shedding the S1 domain connecting it to the host cell receptor. Second, we conclude that the double attachment and the conserved disulfide bridge establish the strong anchoring required for subsequent membrane fusion. Multiple distinct membrane-anchoring elements ensure high avidity and high mechanical strength of FP-membrane binding.read more
Citations
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Identifying Distinct Structural Features of the SARS-CoV-2 Spike Protein Fusion Domain Essential for Membrane Interaction.
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Molecular dynamics studies reveal structural and functional features of the SARS‐CoV‐2 spike protein
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The constellation of cholesterol-dependent processes associated with SARS-CoV-2 infection
TL;DR: The role of cholesterol in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is discussed in the context of two main scenarios: i) the presence of the neutral lipid in cholesterol-rich lipid domains involved in different steps of the viral infection and ii) the alteration of metabolic pathways by the virus over the course of infection as discussed by the authors .
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Different Binding Modes of SARS-CoV-1 and SARS-CoV-2 Fusion Peptides to Cell Membranes: The Influence of Peptide Helix Length
Hujun Shen,Zhenhua Wu,Ling Chen +2 more
TL;DR: It is discovered that the membrane-binding mode would influence the helix length of SARS-CoV-1 FP, while the helIX length ofSARS- co-V-2 FP could be stably maintained in the membranes-bound configurations.
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