Synergistic Activation of TLR7 and 8 Mediated by Reduction of Electrostatic Repulsion

Abstract

Toll-like receptors (TLRs) play central roles in innate immune defense against infection by binding to microbial molecules. TLR7 and TLR8 are highly homologous sensors with an RNA ligand preference for single-stranded RNA (ssRNA). Recent works reveal that these TLR sense degradation products of RNA at two distinct binding sites, designated 1st site and 2nd site, rather than long ssRNA. The highly conserved 1st site is responsible for the binding of nucleosides and the 2nd site confers the oligonucleotide binding. Binding of the oligonucleotide at the 2nd site synergistically enhances the affinity for nucleoside to the 1st site. However, it remains unclear why these ligands synergistically activate TLR7 and TLR8. Here, we performed a molecular dynamics (MD) calculation and successive decomposition analysis to clarify what this synergistic effect is derived from. We demonstrated that the main factor of the synergistic effect during the TLR7 and TLR8 activation processes was the lowering of the LRR dimerization barrier, mainly achieved by the reduction of the electrostatic repulsion with the oligonucleotide binding at the 2nd site.