Structural and functional impact by SARS-CoV-2 Omicron spike mutations

Abstract

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bearing an unusually high number of mutations, has become a dominant strain in many countries within several weeks. We report here structural, functional and antigenic properties of its full-length spike (S) protein with a native sequence in comparison with those of previously prevalent variants. Omicron S requires a substantially higher level of host receptor ACE2 for efficient membrane fusion than other variants, possibly explaining its unexpected cellular tropism. Mutations not only remodel the antigenic structure of the N-terminal domain of the S protein, but also alter the surface of the receptor-binding domain in a way not seen in other variants, consistent with its remarkable resistance to neutralizing antibodies. These results suggest that Omicron S has acquired an extraordinary ability to evade host immunity by excessive mutations, which also compromise its fusogenic capability.

The spike-stabilizing D614G mutation interacts with S1/S2 cleavage site mutations to promote the infectious potential of SARS-CoV-2 variants

“…Omicron carries 33 non-synonymous spikes mutation compared to the Wuhan strain, an unprecedented number of changes that induce a remodeling of the NTD and RBD surfaces, and result in immune evasion from most classes of monoclonal antibodies [51]. These changes also impact the viral entry step, as Omicron infectivity is hampered in conditions of low ACE2 expression [52], a property that may explain the low infectivity of Omicron for lung alveolar tissue [42]. Structurally, the regions that control RBD flipping appear more structured in the Omicron trimer, which may slow down the transition of the RBD to the up position, and thus make ACE2 binding a rate limiting step in viral entry [52].…”

“…These changes also impact the viral entry step, as Omicron infectivity is hampered in conditions of low ACE2 expression [52], a property that may explain the low infectivity of Omicron for lung alveolar tissue [42]. Structurally, the regions that control RBD flipping appear more structured in the Omicron trimer, which may slow down the transition of the RBD to the up position, and thus make ACE2 binding a rate limiting step in viral entry [52]. Residues close to the FCS also appear more structured, which may limit access of the furin enzyme, and account for the low cleavage rate.…”

Hierarchical Computational Modeling and Dynamic Network Analysis of Allosteric Regulation in the SARS-CoV-2 Spike Omicron Trimer Structures: Omicron Mutations Cooperate to Allosterically Control Balance of Protein Stability and Conformational Adaptability

“…confirming the improved binding due to N501Y, Q493R and Q498R mutations. 62 Several other recent cryo-EM structural studies supported the proposed mechanism in which Omicron mutations can stabilize the S trimer in the closed state, allowing for receptor binding while concealing epitopes that are the targets of neutralizing antibodies. 63 The studies reaffirmed that Omicron mutations S477N, T478K and E484A in the flexible RBM region together with K417N account for only a moderate loss of the ACE2 binding while enhancing the neutralization escape potential of the Omicron variant from highly potent antibodies that target the RBM epitopes.…”

Natural variations within the glycan shield of SARS-CoV-2 impact viral spike dynamics

“…The model of the P.1 S glycoprotein ectodomain was built from the cryo-EM structure (PDB 7SBS) [70] with a glycosylation profile matching the site-specific glycan data in this work. The effect of the N188 glycosylation was determined by analyzing the dynamics of two systems, one with a Man5 at N188 in all three protomers and one without the N-glycan at N188 in all three protomers.…”

“…To understand how the protein landscape may shape N188 glycosylation of the P.1 (Gamma) S glycoprotein, we performed extensive sampling through conventional molecular dynamics (MD) of two P.1 S models, one bearing Man5GlcNAc2 (Man5) at N188, and another lacking glycosylation at this site. We reconstructed the P.1 S glycoprotein ectodomain from the cryo-EM structure (PDB 7SBS) [70] with a glycosylation profile matching the site-specific glycan data shown in Figure 5, and with a Man5 at N188 in all three protomers (Supplemental Table 3). The results show that for the entirety of the 1.05 μs molecular dynamics (MD) production run the N188-Man5 occupies a deep cavity in all three protomers (Figure 5A and B), with the core and the 1-3 arm residues engaging in dispersion and hydrogen bonding interactions with different residues lining the interior of the cavity, and the loop above it (residues 171 to 183).…”