Coarse-graining molecular dynamics simulations of TLR4 complexes

Abstract

The toll-like receptor 4 (TLR4) is a transmembrane protein of the innate immune system responsible for recognizing lipopolysaccharides (LPS), essential components of the Gram-negative bacteria outer membrane. The association of LPS to TLR4 promotes its homodimerization, which triggers an inflammatory response. Given its role in the innate immune system, TLR4 is an important target in drug development, especially for the treatment of infections and acute inflammations such sepsis. Recently, TLR4 has also been linked to obesity because of the likely interactions it makes with saturated fatty acids (SFAs) from animal-fat rich diets. Although there are crystallographic structures of the extracellular domains of dimers bound to agonists as well as monomers associated with antagonists the molecular reasons underlying agonist/antagonist action of LPS and SFAs are largely unknown. This topic has been one of the main goals of the postdoctoral project developed by Paulo C. T. Souza (FAPESP scholarship, process 2012/24750-6), in the Skaf Group at the University of Campinas (Brazil). All-atom molecular dynamics (MD) simulations of TLR4 and its coreceptor MD2 associated with LPS and SFAs were performed, aiming to study the dynamics and conformational changes resulting from the association of different ligands. The results of these MD simulations allowed us to create a general model to explain the agonist/antagonist behavior of ligands. Currently, we are interested in computing DeltaG for dimer dissociation of the complete TLR4-MD2 complex inserted in the membrane, with different ligands. However, calculating DeltaG values would require a prohibitively high computational cost if all-atom MD simulations are to be employed. Moreover, there are no models of the intact TLR4-MD2 dimer. Thus, the relative orientation between the TLR4 domains in the dimer are unknown. It is in this context that the research internship abroad with Professor Siewert-Jan Marrink arises. We propose carrying out coarse-graining (CG) MD simulations of TLR4-MD2 complex immersed in a membrane model having the following goals: i) generating an initial model of the intact TLR4 dimer in membrane; ii) comparing the DeltaG of dimerization of TLR4s associated with different ligands. (AU)