The effect of dimerization on the activation and conformational dynamics of adenosine A1 receptor

Abstract

The adenosine A₁ receptor (A₁R) is one of four adenosine receptors in humans, which are involved in the function of the cardiovascular, respiratory and central nervous systems. Experimental results indicate that A₁R can form a homodimer and that the protomer–protomer interaction in the A₁R dimer is related to certain pharmacological characteristics of A₁R activation. In this work, we performed docking, metadynamics simulation, conventional molecular dynamics simulations, Gaussian-accelerated molecular dynamics simulations, potential of mean force calculations, dynamic cross-correlation motions analysis and community network analysis to study the binding mode of 5′-N-ethylcarboxamidoadenosine (NECA) to A₁R and the effect of dimerization on the activation of A₁R. Our results show that NECA binds to A₁R in a similar mode to adenosine in the A₁R crystal structure and NECA in the A_2AR crystal structure. The A₁R homodimer can be activated by one or two agonists with NECA occupying its orthosteric pockets in one (which we call the NECA–A₁R system) or both protomers (which we call the dNECA–A₁R system). In the NECA–A₁R system, activation is predicated in the protomer without NECA bound. In the dNECA–A₁R system, only one protomer achieves the active state. These findings suggest an asymmetrical activation mechanism of the homodimer and a negative cooperativity between the two protomers. We envision that our results may further facilitate the drug development of A₁R.