Fig. 3
a The aligned and superimposed active (PDB ID: 2YDO in blue) and inactive conformations (PDB ID: 5IU4 in grey) of the A2AR protein crystal structures. The Val84-Leu249 Cα distances were measured for the active and inactive conformations and were 14.53 Å and 12.96 Å respectively b The moving average trend-lines (bin-size of 20 frames) are for the Val84-Leu249 Cα distances of the apo structure (PDB ID: 5IU4) and the docked and the co-crystallized structures (PDB ID: 5IU4 and 2YDO use the same color code as 3A) of the A2AR over a simulation of 100 ns. Compounds 1, 5 and CGS21680 are docked into the inactive form of the A2AR protein crystal structure (PDB ID: 5IU4). The variations in the computed distances for compounds 1, 5 and CGS21680 were similar - all increased their average distances over time, moving closer to the average distance observed in the active protein crystal structure (PDB ID: 2YDO). c Violin plots for distance distributions (same color code of Fig. 3b) for the last 450 ns of the simulations shows higher Val84-Leu249 distances for the agonist bound to the A2AR in comparison to the antagonist bound to the A2AR. Hence, the increase in the Val84-Leu249 inter-residue distance upon A2AR agonist binding serves as a promising conformational descriptor for receptor activation by A2AR ligands. A statistical analysis was performed on the distance distributions for the last 450 ns using a Mann-Whitney test and a Kolmogorov-Smirnov test. The differences in medians of the distance distributions for each of the agonists versus the antagonist were significant at a p value < 0.05, and the p value for the Kolmogorov-Smirnov test was < 2.2 × 10− 16