Computational approaches to the dynamics and activation mechanism of Toll-like receptor 4

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Toll-like receptors (TLRs) are pattern recognition receptors involved in innate immunity. In particular, TLR4 binds to lipopolysaccharides (LPS), a membrane constituent of Gram-negative bacteria and, together with MD-2 protein, forms a heterodimeric complex which leads to the activation of the innate immune system response. TLR4 activation has been associated with certain autoimmune diseases, noninfectious inflammatory disorders, and neuropathic pain,suggesting a wide range of possible clinical settings for the application of TLR4 antagonists,while TLR4 agonists would be useful as adjuvants in vaccine development and in cancer immunotherapy.[1,2] Specific molecular features of extracellular, transmembrane, and cytoplasmic domains of TLR4 are crucial for coordinating the complex innate immune signaling pathway. Although structural and biochemical data is currently available for the independent TLR4 domains, this only provides a partial fragmented view, because full-length proteins are flexible entities and dynamics play a key role in their functionality. Therefore, many structural and dynamical features of the TLR4 mode of action remain largely unknown.[3]Computational studies of the different independent domains composing the TLR4 were undertaken, using ab-initio calculations, homology modeling, protein-protein docking, all-atom molecular dynamics simulations, and thermodynamics calculations, to understand the differential domain organization of TLR4. From the information gathered from our independent TLR4 domains studies, we have modeled, by all-atom MD simulations, the structural assembly of plausible full-length TLR4 models embedded into realistic plasma membranes, with different chemical compositions, accounting for the active (agonist) state of the TLR4. We have also applied computational techniques to characterize, at the atomic level, the molecular recognition processes by reported TLR4 modulators, thus proposing a mechanism for their biological activity. These observations unveil relevant molecular aspects involved in the mechanism of receptor activation, and adaptor recruitment in the innate immune pathways, and will promote the discovery of new TLR4 modulators and probes.