Agonist dynamics and conformational selection during microsecond simulations of the A(2A) adenosine receptor

The G-protein-coupled receptors (GPCRs) are a ubiquitous family of signaling proteins of exceptional pharmacological importance. The recent publication of structures of several GPCRs cocrystallized with ligands of differing activity offers a unique opportunity to gain insight into their function. To that end, we performed microsecond-timescale simulations of the A(2A) adenosine receptor bound to either of two agonists, adenosine or UK432097. Our data suggest that adenosine is highly dynamic when bound to A(2A), in stark contrast to the case with UK432097. Remarkably, adenosine finds an alternate binding pose in which the ligand is inverted relative to the crystal structure, forming relatively stable interactions with helices I and II. Our observations suggest new experimental tests to validate our predictions and deepen our understanding of GPCR signaling. Overall, our data suggest an intriguing hypothesis: that the 100- to 1000-fold greater efficacy of UK432097 relative to adenosine arises because UK432097 stabilizes a much tighter neighborhood of active conformations, which manifests as a greater likelihood of G-protein activation per unit time.