An investigation into the allosteric mechanism of GPCR A adenosine receptor with trajectory-based information theory and complex network model.

G protein-coupled receptors (GPCRs), a large superfamily of transmembrane (TM) proteins, allosterically transduce the signal of ligand binding in the extracellular (EC) domain to couple to effector proteins in the intracellular (IC) domain, therefore forming the largest class of drug targets. The A adenosine receptor (AAR), a class-A GPCR, has been extensively studied as it offers numerous possibilities for therapeutic applications. However, the mechanism of allosteric communication between EC and IC domains is not completely clear. In this work, we utilize torsional mutual information to quantify the correlated motions of residue pairs from its molecular dynamics (MD) simulation trajectories, and further use the complex network model to obtain allosteric pipelines and hubs. The identified allosteric communication pipelines mainly transmit the signal from EC domain to the cytoplasmic ends of TM helix 5 (TM5), TM6 and TM7. The allosteric hubs, mostly located at TM5, TM6 and TM7, play an important role in mediating allosteric signal transmission to keep the receptor rigid and prevent G protein from binding to IC domain, which can explain the reason why their mutations distant from ligand-binding site do not affect the ligand binding affinity but affect the ligand efficacy. Additionally, we identify the key residues located in antagonist ZM241385 binding pocket which mediate multiple allosteric pathways and have been experimentally proven to play a critical role in affecting the ligand potency. This study is helpful for understanding the allosteric communication mechanism of AAR, and can provide valuable information for the structure-based drug design of GPCRs.Communicated by Ramaswamy H. Sarma.