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

Abstract

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 A₁, A_2A, A_2B and A₃ 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 hA_2A 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.