title: Lipid A from lipopolysaccharide recognition: structure, dynamics and cooperativity by molecular dynamics simulations.
abstract: Molecular dynamics simulations of Lipid A and its natural precursor Lipid IVA from E.coli have been carried out free in solution, bound to the myeliod differentiation protein 2 (MD2) and in the complex of MD2 with the toll like receptor 4 (TLR4). In addition, simulations of the ligand free MD2 and MD2-TLR4 complex were performed. A structural and energetic characterization of the bound and unbound states of Lipid A/IVA was generated. As the crystal structures depict, the main driving force for MD2-Lipid A/IVA are the hydrophobic interactions between the aliphatic tails and the MD2 cavity. The charged phosphate groups do strongly interact with positively charged residues, located at the surface of MD2. However, they are not essential for keeping the lipids in the cavity, indicating a more prominent role in binding recognition and ionic interactions with TLR4 at the MD2/TLR4 interface. Interestingly, in the absence of any ligand MD2 rapidly closes, blocking the binding cavity. The presence of TLR4, though changing the dynamics, was not able to impede the aforementioned closing event. We hypothesize that fluctuations of the H1 region are essential for this phenomenon, and it is plausible that an equilibrium between the open and closed states exists, although the lengths of our simulations are not sufficient to encompass the reversible process. The MD2/Lipid A-TLR4 complex simulations show that the presence of the ligand energetically stabilizes the complex relative to the ligand-free structures, indicating cooperativity in the binding process.
authors.affiliation: Department of Medical Sciences and Process Engineering, Institute of Molecular Modelling and Simulation, University of Natural Resources and Life Sciences, Vienna, Austria.
authors.forename: Jose Antonio
authors.initials: JA
authors.lastname: Garate
authors.forename: Chris
authors.initials: C
authors.lastname: Oostenbrink
mesh_terms: D004926:Escherichia coli / Q000737:chemistry* / Q000502:physiology; D004927:Escherichia coli Infections / Q000382:microbiology; D006017:Glycolipids / Q000737:chemistry / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D051218:Lymphocyte Antigen 96 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D013816:Thermodynamics; D051197:Toll-Like Receptor 4 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006017:Glycolipids; C495377:LY96 protein, human; D008050:Lipid A; D051218:Lymphocyte Antigen 96; D051197:Toll-Like Receptor 4; C040142:lipid A precursors, bacterial