Molecular dynamics simulation at high sodium chloride concentration: Toward the inactive conformation of the human adenosine A2A receptor

The recently solved crystal structure of the human adenosine A2A receptor (hA2AR) shows the characteristics of a partially activated state. Experimental data suggests that high sodium chloride concentration shifts hA2AR to the inactive state. We found that molecular dynamics simulations at high sodium chloride concentration result in an inactive form of hA2AR reflected in the reformation of the "ionic lock" (Arg¹⁰²(3.50)-Glu ²²⁸(6.30)) as well as in the reduction of the RC-RC distance between the intracellular sides of transmembrane helices 3 and 6 (TM3 and TM6). Interestingly, no such stabilization effect was observed at physiological concentrations. Our results suggest that the effect of high sodium chloride concentration might be exploited to generate an inactive state of hA2AR, which is more favorable for identifying pharmacologically relevant antagonists or inverse agonists. © 2010 American Chemical Society.