Exploring the recognition pathway at the human A2A adenosine receptor of the endogenous agonist adenosine using supervised molecular dynamics simulations

Adenosine is a naturally occurring purine nucleoside that exerts a variety of important biological functions through the activation of four G protein-coupled receptor (GPCR) isoforms, namely the A(1), A(2A), A(2B) and A(3) adenosine receptors (ARs). Recently, the X-ray structure of adenosine-bound hA(2A) AR has been solved, thus providing precious structural details on receptor recognition and activation mechanisms. To date, however, little is still known about the possible recognition pathway the endogenous agonist might go through while approaching the hA2A AR from the extracellular environment. In the present work, we report the adenosine-hA(2A) AR recognition pathway through the analysis of a series of Supervised Molecular Dynamics (SuMD) trajectories. Interestingly, a possible energetically stable meta-binding site has been detected and characterized.