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Dynamics and functions of G-protein coupled receptors (GPCRs) are accuratelyregulated by the type of ligands that bind to the orthosteric or allostericbinding sites. To glean the structural and dynamical origin of ligand-dependentmodulation of GPCR activity, we performed total $\sim$ 5 $\mu$sec moleculardynamics simulations of A$_{2A}$ adenosine receptor (A$_{2A}$AR) in its apo,antagonist-bound, and agonist-bound forms in an explicit water and membraneenvironment, and examined the corresponding dynamics and correlation betweenthe 10 key structural motifs that serve as the allosteric hotspots inintramolecular signaling network. We dubbed these 10 structural motifs "binaryswitches" as they display molecular interactions that switch between twodistinct states. By projecting the receptor dynamics on these binary switchesthat yield $2^{10}$ microstates, we show that (i) the receptors in apo,antagonist-bound, and agonist-bound states explore vastly differentconformational space; (ii) among the three receptor states the apo stateexplores the broadest range of microstates; (iii) in the presence of theagonist, the active conformation is maintained through coherent couplings amongthe binary switches; and (iv) to be most specific, our analysis shows thatW246, located deep inside the binding cleft, can serve as both an agonistsensor and actuator of ensuing intramolecular signaling for the receptoractivation.Finally, our analysis of multiple trajectories generated byinserting an agonist to the apo state underscores that the transition of thereceptor from inactive to active form requires the disruption of ionic-lock inthe DRY motif.

Communication over the network of binary switches regulates the activation of A$_{2A}$ adenosine receptor