SuMD trajectories Videos Video 1: Sodium binding pathway on the antagonist-bound state of A2AR. The video is composed of four synchronized and animated panels that depict the molecular trajectory obtained by the SuMD simulation considering different aspects of the simulation. The time evolution is reported in a nanosecond. In the first panel (upper-left), the molecular representation of the macromolecular system is shown. The A2AR antagonist-bound state backbone is represented by the ribbon style (cyan colour) and the residues within 4 Å of sodium ion during the entire simulation are dynamically shown. Na+ is rendered showing its VdW volume in yellow. In the second panel (upper-right), the dynamic distance of sodium center of mass (CM) from the A2AR allosteric binding site during the trajectory is reported. In the third panel (lower-left), the MMGBSA energy profile is reported. The animated red circle highlights the value of the corresponding frame. The trend is depicted by a continuous black line obtained by smoothing the raw data (grey circles) using a Bezier curve procedure. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 A2AR residues most contacted by sodium during the whole simulation. Video 2: Adenosine different binding pathways collection on the two relevant states of A2AR The video is composed of two panels, which summarizes the recognition process of the adenosine agonist, sampled by means of the supervised molecular dynamics methodology, in the two pharmacologically relevant states of the receptor. In particular, on the right side are shown simultaneously all ten replicas collected starting from the agonist-bound conformation of the A2AR (pink ribbon). The meta-binding site located at the level of the ECL2 and the orthosteric binding site were highlighted. On the left side are represented simultaneously all ten replicas collected starting from the antagonist-bound conformation of the A2AR (cyan ribbon). The meta-binding site located at the level of the ECL2 and the extracellular receptor vestibule were highlighted. Video 3: Adenosine binding pathway on the agonist-bound state of A2AR. The video is composed of four synchronized and animated panels that depict the molecular trajectory obtained by the SuMD simulation considering different aspects of the simulation. The time evolution is reported in a nanosecond. In the first panel (upper-left), the molecular representation of the macromolecular system is shown. The A2AR agonist-bound state backbone is represented by the ribbon style (pink colour) and the residues within 4 Å of sodium ion during the entire simulation are dynamically shown. Adenosine molecule is rendered by orange carbon atoms and by a transparent surface. In the second panel (upper-right), the dynamic distance of agonist center of mass (CM) from the A2AR allosteric binding site during the trajectory is reported. In the third panel (lower-left), the MMGBSA energy profile is reported. The animated red circle highlights the value of the corresponding frame. The trend is depicted by a continuous black line obtained by smoothing the raw data (grey circles) using a Bezier curve procedure. In the fourth panel (lower-right) cumulative electrostatic interactions are reported for the 15 A2AR residues most contacted by adenosine during the whole simulation.