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. 2023 Feb 6;15(2):447.
doi: 10.3390/v15020447.

SARS-CoV-2 Omicron Subvariants Balance Host Cell Membrane, Receptor, and Antibody Docking via an Overlapping Target Site

Michael Overduin  1 , Rakesh K Bhat  1 , Troy A Kervin  1
Affiliations

SARS-CoV-2 Omicron Subvariants Balance Host Cell Membrane, Receptor, and Antibody Docking via an Overlapping Target Site

Michael Overduin et al. Viruses. .

Abstract

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are emerging rapidly and offer surfaces that are optimized for recognition of host cell membranes while also evading antibodies arising from vaccinations and previous infections. Host cell infection is a multi-step process in which spike heads engage lipid bilayers and one or more angiotensin-converting enzyme 2 (ACE-2) receptors. Here, the membrane binding surfaces of Omicron subvariants are compared using cryo-electron microscopy (cEM) structures of spike trimers from BA.2, BA.2.12.1, BA.2.13, BA.2.75, BA.3, BA.4, and BA.5 viruses. Despite significant differences around mutated sites, they all maintain strong membrane binding propensities that first appeared in BA.1. Both their closed and open states retain elevated membrane docking capacities, although the presence of more closed than open states diminishes opportunities to bind receptors while enhancing membrane engagement. The electrostatic dipoles are generally conserved. However, the BA.2.75 spike dipole is compromised, and its ACE-2 affinity is increased, and BA.3 exhibits the opposite pattern. We propose that balancing the functional imperatives of a stable, readily cleavable spike that engages both lipid bilayers and receptors while avoiding host defenses underlies betacoronavirus evolution. This provides predictive criteria for rationalizing future pandemic waves and COVID-19 transmissibility while illuminating critical sites and strategies for simultaneously combating multiple variants.

Keywords: MODA; SARS-CoV-2; coronavirus; delta; lipid bilayer; membrane docking; omicron; spike protein; variants.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hypothetical model of host cell membrane binding by Omicron subvariant spikes. A network of spike states based on Omicron subvariant structures is shown. Those states populated insufficiently to be seen by cryo-EM are whited out. The unbound RBD modules flicker between up and down states (tall and short blue rectangles, respectively) to yield open state 1.1. Additionally, drawn are the NTDs (blue triangles) and C-terminal remainder of the S subunits (blue line) that span the viral membrane (light grey bar). The host cell membrane (red) is engaged in states 2 and above of the spike trimer structure, which are predicted to prefer binding to concave membranes. The membrane-tethered spike trimer can bind a single ACE-2 receptor (green circle) on the host cell surface in state 3, a second ACE-2 molecule in state 4, and a third ACE-2 molecule to form prefusion state 5. This leads to proposed state 6, where ACE-2-spike complexes stabilize the membrane contact site while a cleaved spike trimer inserts into the host cell surface, drawing it close to the viral membrane to merge lipid bilayers [44]. Adapted from [11].
Figure 2
Figure 2
Comparison of membrane binding by BA.2 spike conformational states. (A) The structures of five states are shown as blue surfaces with residues having significant and substantial membrane binding propensities coloured pink and red, respectively, as indicated in the scale. The PDB entries are labeled below the structures. The viral membrane is shown as a grey slab, and the spike trimer is tilted to position the membrane binding surfaces towards the host cell above. (B) The heatmap shows the membrane binding propensities of residues in BA.2 spike trimer structures, with the RBD position and ACE-2 occupancy labelled on the left side. Positions are coloured light blue–yellow–red to indicate MODA scores from 0-50-2000 as in the scale, while light grey indicates missing coordinates.
Figure 3
Figure 3
Comparison of membrane binding by BA.2.75 spike conformational states. (A) The residues with moderate (pink) and substantial (red) membrane binding propensities in the SARS-CoV-2 variant BA.2.75’s spike protein trimer in its progressive closed, open, and singly and doubly ACE-2 bound states (PDBs: 8gs6, 7yqt, 7yr2, 7yr3) are shown in the side views from left to right. The viral membrane is shown as a grey slab, and the spike trimer is tilted to position host membrane binding interfaces above. Residues are labelled and coloured pink-red based on MODA scores of 20–40+. (B) The heatmap shows the membrane binding propensities of S residues. RBD position and ACE-2 occupancy are labelled left of the map, and the S state is on the right. Positions are coloured light blue–yellow–red to indicate MODA scores from 0-50-2000, as in the lower right scale, while grey indicates missing positions in the PDB files. The positions of the NTD, RBD, fusion peptide (FP), and heptad repeat 1 (HR1) are shown below.
Figure 4
Figure 4
Membrane binding surfaces of closed BA.2.12.1, BA.2.13, BA.3, and BA.4/5 variants spike trimers. (A) The residues with moderate (pink) and substantial (red) membrane binding propensities in the closed states of spike trimer structures of the labelled variants are shown in top (above) and side (below) views of the surfaces. (B) Heatmap showing the membrane propensity scores for each residue of each of the three subunits of the closed spike structures, which are labelled along with the numbering of the variant sequences above and the domains beneath.
Figure 5
Figure 5
Membrane binding by conformational states of SARS-CoV-2 Omicron variants. (A) The average membrane binding propensities of the RBD subunit of the closed spike trimer structures are shown for each of the variants. (B) The average membrane binding propensities of the subunits of the closed, open, singly, doubly, and triply ACE-2-bound forms (states 1.0, 1.1, 3.2, 4.2, and 5, Figure 1) are shown for spike trimer structures (Table 2) of the Omicron BA.2 and BA.2.75 subvariants and (C) dipole moments of the closed structures of the Omicron subvariant spike ectodomain trimers, with standard deviations shown unless there are insufficient numbers of structures to calculate this. (D) The average dipole moments of the closed structures of the Omicron variant spike ectodomain trimers are linearly correlated with the ACE-2 binding affinities of their RBD domains [7,27,28].
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This research was funded by the NSERC Discovery Grant (RGPIN-2018-04994) and Campus Alberta Innovates Program (#RCP-12-002C) grants to M.O.