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Abstract
Toll-like receptors (TLRs) form the first barrier of the innate immune system. TLR8 is an important target to treat autoimmune diseases, since its ligand-induced degree of activation regulates immune response and associated hyperinflammation. Molecular dynamics (MD) simulations have been used to investigate interactions of TLRs with ligands, but the mechanism of ligand unbinding still remains elusive. We therefore applied τ-Random Acceleration Molecular Dynamics (τRAMD) simulations to characterize the unbinding paths of one TLR8 agonist and five TLR8 antagonists. Data analysis of the simulations led to the discovery of two possible unbinding pathways, the internal pathway, directed towards the toll-interleukin-1 receptor (TIR) domain, and the external pathway, pointing away from the TIR domain. Remarkably, some ligands showed clear path preferences: the TLR8 agonist exited through the external unbinding pathway only, while the cationic antagonists exited through the internal pathway only. The neutral antagonists used both pathways. The mechanistic insights obtained can assist in the design of improved TLR modulators.
Supplementary materials
Title
Supplementary Information Agonists and antagonists show different unbinding paths from the TLR8 receptor
Description
Scatter plots of minimum distances between the ligand and specific residues which were used to assist unbinding pathway classification (Figure S1); Chi angle calculation of Tyr353 for the first and last five frames of τRAMD trajectories of ligand 1 (Figure S2); Residence times of ligand 1 (Figure S3); Distribution of residence times of ligand 1 (Figure S4); Residence times of ligand 2 (Figure S5); Distribution of residence times of ligand 2 (Figure S6); Residence times of ligand 3 (Figure S7); Distribution of residence times of ligand 3 (Figure S8); Residence times of ligand 4 (Figure S9); Distribution of residence times of ligand 4 (Figure S10); Residence times of ligand 5 (Figure S11); Distribution of residence times of ligand 5 (Figure S12); Residence times of ligand 6 (Figure S13); Distribution of residence times of ligand 6 (Figure S14);
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Supplementary weblinks
Title
Github repository for the data used in TLR8 unbinding pathways
Description
Contains all of the data used for the preparation of the protein structures, ligand parameterization, molecular dynamics simulations and simulations analysis.
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