Structural insights into TLR4 activation by SARS-CoV-2 spike protein: implications for inflammatory response...

Area of Science:

• Immunology
• Virology
• Structural Biology

Background:

• Toll-like receptor 4 (TLR4) complexed with myeloid differentiation factor 2 (MD2) is crucial for innate immunity during viral infections.
• Viral glycoproteins, like the SARS-CoV-2 spike (S) protein, may inappropriately activate TLR4, potentially causing cytokine storms.

Purpose of the Study:

• To investigate the molecular interactions between the SARS-CoV-2 spike protein (monomer and trimer) and the TLR4/MD2 receptor complex.
• To elucidate the structural basis for potential aberrant TLR4 activation by the spike protein.

Main Methods:

• Utilized a comprehensive in silico framework, including protein-protein docking.
• Performed extended molecular dynamics simulations (500 ns), interaction profiling, principal component analysis (PCA), and binding-affinity calculations.

Main Results:

• The S1 subunit, specifically the receptor-binding domain (RBD) and N-terminal domain (NTD), was identified as the primary binding interface for TLR4/MD2.
• The spike monomer demonstrated more stable and stronger interactions with TLR4/MD2 compared to the trimer.
• Identified specific hotspot residues and potential roles of glycosylation sites in modulating receptor interactions.

Conclusions:

• The SARS-CoV-2 spike protein engages TLR4/MD2 via domain-specific interactions, primarily through its S1 subunit.
• These interactions, particularly with the monomeric form, may contribute to aberrant innate immune signaling and cytokine storms.
• Identified potential therapeutic targets for modulating TLR4-mediated immune responses.