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. 2024 Mar;22(1):100347.
doi: 10.1016/j.jgeb.2023.100347. Epub 2024 Jan 22.

SARS-CoV-2 Omicron Spike shows strong binding affinity and favourable interaction landscape with the TLR4/MD2 compared to other variants

Chiranjib Chakraborty  1 , Bidyut Mallick  2 , Manojit Bhattacharya  3 , Siddappa N Byrareddy  4
Affiliations

SARS-CoV-2 Omicron Spike shows strong binding affinity and favourable interaction landscape with the TLR4/MD2 compared to other variants

Chiranjib Chakraborty et al. J Genet Eng Biotechnol. 2024 Mar.

Abstract

Emergences of SARS-CoV-2 variants have made the pandemic more critical. Toll-like receptor 4 (TLR4) recognizes the molecular patterns of pathogens and activates the production of proinflammatory cytokines to restrain the infection. We have identified a molecular basis of interaction between the Spike and TLR4 of SARS-CoV-2 and its present and past VOCs (variant- of concern) through in silico analysis. The interaction of wild type Spike with TLR4 showed 15 number hydrogen bonds formation. Similarly, the Alpha variants' Spike with the TLR4 has illustrated that 14 hydrogen bonds participated in the interaction. However, the Delta Spike and TLR4 interaction interface showed that 17 hydrogen bonds were formed during the interaction. Furthermore, Omicron S-glycoprotein and TLR4 interaction interface was depicted (interaction score: -170.3), and 16 hydrogen bonds were found to have been formed in the interaction. Omicron S-glycoprotein shows stronger binding affinity with the TLR4 than wild type, Alpha, and Delta variants. Similarly, the Alpha Spike shows higher binding affinity with TLR4 than the wild type and Delta variant. Now, it is an open question of the molecular basis of the interaction of Spike and TLR4 and the activated downstream signaling events of TLR4 for SARS-CoV-2 and its variants.

Keywords: Alpha: Delta; Omicron; SARS-CoV-2; Spike protein; Toll-like receptor 4.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
The figure shows the structural conformations of the Spike protein of wild type, Alpha, Delta, Omicron, and TLR4/MD2 complex (a) Structure of wild type Spike protein. The structure is developed using a PDB file with PDB id: 7BNN (b) Structure of TLR4/MD2 complex. The structure is developed by using a PDB file with PDB id: 4G8A (c) S-glycoprotein for the Alpha variant. Here, we have created E484K, S494P, N501Y mutations in the wild type S-glycoprotein. (d) S-glycoprotein for the Delta variant. Here, we have inserted L452R, E478K, T19T, G142D, R158G mutations in the wild type S-glycoprotein (e) S-glycoprotein for the Omicron variant. Here, we have inserted N440K, G446S, S477N, T478K, E484A, Q493K, G496S, Q498R, N501Y, Y505H G339D, S371L, S373P, S375F, K417N, G142D, Δ143–145, A67V, Δ69-70, T95I, del 211, L212I, T547K.
Fig. 2
Fig. 2
The figure shows the structural conformations after the interaction of Spike protein (wild type, Alpha, Delta, and Omicron) and TLR4/MD2 complex. (a) The figure shows the possible binding configurations and the conformations are: (i) Interaction of TLR4 with RBD of B chain & N-terminal of the same chain (ii) Interaction of TLR4 with RBD of B chain & N-terminal of C-chain. However, the second configuration has shown a better binding affinity than the other orientation. (b) Configuration of the interaction between wild type Spike and TLR4 (c) Configuration of the interaction between Alpha Spike and TLR4 (d) Configuration of the interaction between Delta Spike and TLR4 (e) Configuration of the interaction between Omicron Spike and TLR4.
Fig. 3
Fig. 3
A hypothetical schematic diagram shows S-glycoprotein and TLR4 interaction and feedback loop generation. It also shows activation of downstream signaling event by the interaction Omicron Spike via TLR4. (a) The hypothetical figure demonstrates the increased ACE2 expression and S-protein and ACE2 interaction through positive feedback loop generation. The figure also shows the activation of downstream signaling event by Omicron Spike via TLR4. (b) The figure depicts the interaction of Omicron Spike via TLR4, which further activates the downstream signaling for the immune response generation, cytokine signaling, T-cell and B-cell activation.
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