title: Insights into the species-specific TLR4 signaling mechanism in response to Rhodobacter sphaeroides lipid A detection.
abstract: TLR4 in complex with MD2 senses the presence of lipid A (LA) and initiates a signaling cascade that curb the infection. This complex is evolutionarily conserved and can initiate the immune system in response to a variety of LAs. In this study, molecular dynamics simulation (25 ns) was performed to elucidate the differential behavior of TLR4/MD2 complex in response to Rhodobacter sphaeroides lipid A (RsLA). Penta-acyl chain-containing RsLA is at the verge of agonist (6 acyl-chains) and antagonist (4 acyl-chains) structure, and activates the TLR4 pathway in horses and hamsters, while inhibiting in humans and murine. In the time-evolved coordinates, the promising factors that dictated the differential response included the local and global mobility pattern of complexes, solvent-accessible surface area of ligand, and surface charge distributions of TLR4 and MD2. We showed that the GlcN1-GlcN2 backbone acquires agonist (3FXI)-like configurations in horses and hamsters, while acquiring antagonist (2E59)-like configurations in humans and murine systems. Moreover, analysis of F126 behavior in the MD2 F126 loop (amino acids 123-129) and loop EF (81-89) suggested that certain sequence variations also contribute to species-specific response. This study underlines the TLR4 signaling mechanism and provides new therapeutic opportunities.
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Muhammad Ayaz
authors.initials: MA
authors.lastname: Anwar
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Suresh
authors.initials: S
authors.lastname: Panneerselvam
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Masaud
authors.initials: M
authors.lastname: Shah
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, 443-749, Korea.
authors.forename: Sangdun
authors.initials: S
authors.lastname: Choi
mesh_terms: D000818:Animals; D006224:Cricetinae; D006736:Horses; D006801:Humans; D008024:Ligands; D008050:Lipid A / Q000737:chemistry / Q000378:metabolism*; D051218:Lymphocyte Antigen 96 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012242:Rhodobacter sphaeroides / Q000378:metabolism*; D015398:Signal Transduction; D013045:Species Specificity; D055672:Static Electricity; D013816:Thermodynamics; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D008024:Ligands; D008050:Lipid A; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4