Full‐Atom Model of the Agonist LPS‐Bound Toll‐like Receptor 4 Dimer in a Membrane Environment

The Toll‐like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD‐2) innate immunity system is a membrane receptor of paramount importance as therapeutic target. Its assembly, upon binding of Gram‐negative bacteria lipopolysaccharide (LPS), and also dependent on the membrane composition, finally triggers the immune response cascade. We have combined ab‐initio calculations, molecular docking, all‐atom molecular dynamics simulations, and thermodynamics calculations to provide the most realistic and complete 3D models of the active full TLR4 complex embedded into a realistic membrane to date. Our studies give functional and structural insights into the transmembrane domain behavior in different membrane environments, the ectodomain bouncing movement, and the dimerization patterns of the intracellular Toll/Interleukin‐1 receptor domain. Our work provides TLR4 models as reasonable 3D structures for the (TLR4/MD‐2/LPS)(2) architecture accounting for the active (agonist) state of the TLR4, and pointing to a signal transduction mechanism across cell membrane. These observations unveil relevant molecular aspects involved in the TLR4 innate immune pathways and will promote the discovery of new TLR4 modulators.