Abstract:Objectives
The Covid-19 pandemic has been marked by sudden outbreaks of SARS-CoV-2 variants harboring mutations in both the N-terminal (NTD) and receptor binding (RBD) domains of the spike protein. The goal of this study was to predict the transmissibility of SARS-CoV-2 variants from genomic sequence data.
Methods
We used a target-based molecular modeling strategy combined with surface potential analysis of the NTD and RBD.
Results
We observe… Show more
“…This is likely due to closer positioning and flexibility of RBD residues such as Q493. Recent reports have suggested that the E484K mutation may enhance ACE2 binding via increasing electrostatic complementarity between ACE2 and the RBD (Dejnirattisai et al, 2021;Fantini et al, 2021), and the structures reported here are consistent with that hypothesis. The combination of the L452R mutation with either Beta or Gamma variant RBD mutations (D614G + N501Y + E484K + K417N/T) did not further increase ACE2 affinity.…”
The recently emerged SARS-CoV-2 Beta (B.1.351) and Gamma (P.1) variants of concern (VoCs) include a key mutation (N501Y) found in the Alpha (B.1.1.7) variant that enhances affinity of the spike protein for its receptor, ACE2. Additional mutations are found in these variants at residues 417 and 484 that appear to promote antibody evasion. In contrast, the Epsilon variants (B.1.427/429) lack the N501Y mutation, yet exhibit antibody evasion. We have engineered spike proteins to express these RBD VoC mutations either in isolation, or in different combinations, and analyze the effects using biochemical assays and cryo-EM structural analyses. Overall, our findings suggest that the emergence of new SARS-CoV-2 variant spikes can be rationalized as the result of mutations that confer either increased ACE2 affinity, increased antibody evasion, or both, providing a framework to dissect the molecular factors that drive VoC evolution.
“…This is likely due to closer positioning and flexibility of RBD residues such as Q493. Recent reports have suggested that the E484K mutation may enhance ACE2 binding via increasing electrostatic complementarity between ACE2 and the RBD (Dejnirattisai et al, 2021;Fantini et al, 2021), and the structures reported here are consistent with that hypothesis. The combination of the L452R mutation with either Beta or Gamma variant RBD mutations (D614G + N501Y + E484K + K417N/T) did not further increase ACE2 affinity.…”
The recently emerged SARS-CoV-2 Beta (B.1.351) and Gamma (P.1) variants of concern (VoCs) include a key mutation (N501Y) found in the Alpha (B.1.1.7) variant that enhances affinity of the spike protein for its receptor, ACE2. Additional mutations are found in these variants at residues 417 and 484 that appear to promote antibody evasion. In contrast, the Epsilon variants (B.1.427/429) lack the N501Y mutation, yet exhibit antibody evasion. We have engineered spike proteins to express these RBD VoC mutations either in isolation, or in different combinations, and analyze the effects using biochemical assays and cryo-EM structural analyses. Overall, our findings suggest that the emergence of new SARS-CoV-2 variant spikes can be rationalized as the result of mutations that confer either increased ACE2 affinity, increased antibody evasion, or both, providing a framework to dissect the molecular factors that drive VoC evolution.
“…Such a charge distribution promotes the spike corona stability and enhances the virion attachment to receptors and surfaces, mostly negatively charged, 20 eg, gangliosides-rich lipid rafts. 21 …”
“…The antibody studied is 1054 (pdb file #7LAB) which has been isolated from a symptomatic Covid-19 patient 1 . Molecular modelling simulations were performed as previously described 2 . Two currently circulating Delta variants were investigated, with the following mutational patterns in the NTD : - G142D/E154K (B.1.617.1) - T19R/E156G/del157/del158/A222V (B.1.617.2) …”
mentioning
confidence: 99%
“…Overall, the energy of interaction of the NTD-raft complex was raised from -399 kJ.mol â1 in absence of the antibody to -457 kJ.mol â1 with the antibody. By clamping the NTD and the lipid raft, the antibody reinforces the attachment of the spike protein to the cell surface and thus facilitates the conformational change of the RBD which is the next step of the virus infection process 2 . Figure 1 Infection enhancing antibodies recognize the NTD of Delta variants.…”
Antibody dependent enhancement (ADE) of infection is a safety concern for vaccine strategies. In a recent publication, Li et al. (Cell 184Â :1-17, 2021) have reported that infection-enhancing antibodies directed against the N-terminal domain (NTD) of the SARS-CoV-2 spike protein facilitate virus infection in vitro, but not in vivo. However, this study was performed with the original Wuhan/D614G strain. Since the Covid-19 pandemic is now dominated with Delta variants, we analyzed the interaction of facilitating antibodies with the NTD of these variants. Using molecular modelling approaches, we show that enhancing antibodies have a higher affinity for Delta variants than for Wuhan/D614G NTDs. We show that enhancing antibodies reinforce the binding of the spike trimer to the host cell membrane by clamping the NTD to lipid raft microdomains. This stabilizing mechanism may facilitate the conformational change that induces the demasking of the receptor binding domain. As the NTD is also targeted by neutralizing antibodies, our data suggest that the balance between neutralizing and facilitating antibodies in vaccinated individuals is in favor of neutralization for the original Wuhan/D614G strain. However, in the case of the Delta variant, neutralizing antibodies have a decreased affinity for the spike protein, whereas facilitating antibodies display a strikingly increased affinity. Thus, ADE may be a concern for people receiving vaccines based on the original Wuhan strain spike sequence (either mRNA or viral vectors). Under these circumstances, second generation vaccines with spike protein formulations lacking structurally-conserved ADE-related epitopes should be considered.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citationsâcitations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
