  Dynamics and functions of G-protein coupled receptors (GPCRs) are accurately
regulated by the type of ligands that bind to the orthosteric or allosteric
binding sites. To glean the structural and dynamical origin of ligand-dependent
modulation of GPCR activity, we performed total $\sim$ 5 $\mu$sec molecular
dynamics simulations of A$_{2A}$ adenosine receptor (A$_{2A}$AR) in its apo,
antagonist-bound, and agonist-bound forms in an explicit water and membrane
environment, and examined the corresponding dynamics and correlation between
the 10 key structural motifs that serve as the allosteric hotspots in
intramolecular signaling network. We dubbed these 10 structural motifs "binary
switches" as they display molecular interactions that switch between two
distinct states. By projecting the receptor dynamics on these binary switches
that yield $2^{10}$ microstates, we show that (i) the receptors in apo,
antagonist-bound, and agonist-bound states explore vastly different
conformational space; (ii) among the three receptor states the apo state
explores the broadest range of microstates; (iii) in the presence of the
agonist, the active conformation is maintained through coherent couplings among
the binary switches; and (iv) to be most specific, our analysis shows that
W246, located deep inside the binding cleft, can serve as both an agonist
sensor and actuator of ensuing intramolecular signaling for the receptor
activation.Finally, our analysis of multiple trajectories generated by
inserting an agonist to the apo state underscores that the transition of the
receptor from inactive to active form requires the disruption of ionic-lock in
the DRY motif.
