Insights into the species-specific TLR4 signaling mechanism in response to Rhodobacter sphaeroides lipid A detection

摘要: TLR4 in complex with MD2 senses the presence of lipid A (LA) and initiates a signaling cascade that curb infection. This is evolutionarily conserved can initiate immune system response to variety LAs. In this study, molecular dynamics simulation (25 ns) was performed elucidate differential behavior TLR4/MD2 Rhodobacter sphaeroides (RsLA). Penta-acyl chain-containing RsLA at verge agonist (6 acyl-chains) antagonist (4 structure, activates pathway horses hamsters, while inhibiting humans murine. time-evolved coordinates, promising factors dictated included local global mobility pattern complexes, solvent-accessible surface area ligand, charge distributions MD2. We showed GlcN1-GlcN2 backbone acquires (3FXI)-like configurations acquiring (2E59)-like murine systems. Moreover, analysis F126 loop (amino acids 123-129) EF (81-89) suggested certain sequence variations also contribute species-specific response. study underlines mechanism provides new therapeutic opportunities.