TLR4 associated with MD2 protein and lipopolysaccharide LPS) and provided key insights into the orientation and interaction of LRR (named ECD in the paper), TM, and TIR domains with respect to the dipalmitoylphosphatidylcholine (DPPC) bilayer. To reach these results, they successfully applied homology modelling methods, followed by protein-protein docking and MD simulations. Additionally, they used molecular docking and binding free energy calculations to get insight into the binding of the TAK-242 ligand with the TLR4-TIR dimer. They showed that each domain of TLR4 exhibits several structural transitions. The results revealed that LRR and TIR domains may be partially immersed in the membrane bilayer and that the TM domain tilts and bends to overcome the hydrophobic mismatch with the bilayer core. The authors claimed that the dynamic properties of TLR4-LRR had little effect on the interactions between LPS and MD2. For the TLR4-TM, the authors pointed out the possibility of an alternate dimerisation or a potential oligomerisation interface, as previously found for TLR3-TM analyses indicated that the TLR3-TIR homodimer built from the TLR6-TIR structure led to obtaining a full-length receptor structure with the stability necessary to maintain key intermolecular interactions with the ligand and with the membrane. Furthermore, they showed that flexible juxtamembrane loops of TLR3 allow for the simultaneous bending of the LRR and TIR domains on both surfaces of the membrane. They also observed that the complex immersed in the bilayer progressively tilted on the bilayer surface due to the electrostatic attraction between the charged parts of both the protein and phospholipids from the bilayer. In that case, the LRR-NT was only partially absorbed by the lipid headgroups. That was in contrast to the LRR-NT from their previously reported TLR4 model which was completely buried in the bilayer surface.