GPCR AAR agonist binding and induced conformation changes of functional switches

Agonist binding of A adenosine receptor (AAR) shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing AAR selectively binding agonists. Using molecular dynamics (MD) simulations, we have studied the interactions between AAR and its agonist (adenosine), and analyzed the induced dynamic behaviors of the receptor. Key residues interacting with adenosine are identified: A63, I66, V84 , L85, T88, F168, M177, L249, H250, and N253 interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L167 is observed, which supports our previous findings that L167 is an antagonist specific binding reside. The dynamic behaviors of agonist bound AAR are found to be different from apo-AAR in three typical functional switches: (i) tight "ionic lock" forms in adenosine-AAR, but it is in equilibrium between formation and breakage in apo-AAR; (ii) the "rotamer toggle switch", T88/F242/W246, adopted different rotameric conformations in adenosine-AAR and apo-AAR; (iii) adenosine-AAR has a flexible intracellular loop 2 (IC2) and α-helical IC3, while apo-AAR preferred α-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic functional switches in adenosine-AAR and apo-AAR. © 2014 Chinese Physical Society.