The novel pathogenic SARS-CoV-2, an enveloped RNA virus responsible for the Covid-19 disease outbreak, enters the host cell through the spike ‘S’ glycoprotein [Walls 2020, Wang2020]. This is a membrane-anchored trimer composed of two subunits, the N-terminal receptor-binding ‘S1’ segment and the C-terminal ‘S2’ domain (CTD) [Chan2020, Xiao2004, Wang 2020]. Once the ‘S’ protein binds to the h-ACE2 embedded in the host cell surface, the (ligand-receptor) complex undergoes proteolytic cleavage at specific positions, resulting in a hinge-like conformational change in its ‘S2’ subunit that is required for the activation of the fusion potential of the protein [Gadlage2010]. In particular, the S2 subunit mediates fusion between the viral and host cell membranes [Du2009] building on the efforts of the fusion peptides (FPs). They act as a catalyst facilitating the initialization stage of membrane fusion by inducing long-range membrane reorganization resulting in membrane bending.<br/>Recreating the scenario of viral entry process by an in vitro model system studied by neutron reflectivity has been therefore very insightful in providing a physical and thermodynamic description of the viral fusion mechanism. Simplifying the system down to its core elements: synthetic peptides, which mimic overlapping sections of the SARS-Cov-2 S2 fusion region, specific natural perdeuterated lipids extracted from yeast cells, which reproduce the composition of the plasma membrane in the form of monolayers and bilayers, and by taking advantage of the adequate isotopic selective labelling strategy has allowed us to enhance the sensitivity on the structural features of the binding mechanism.

Interaction of CoV-2 peptide responsible for fusion (S2 peptide) with mammalian membranes by neutron reflectometry

ACS Spring Meeting 2021

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