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

The adenosine A(1) receptor (A(1)R) 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 A(1)R can form a homodimer and that the protomer-protomer interaction in the A(1)R dimer is related to certain pharmacological characteristics of A(1)R 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 A(1)R and the effect of dimerization on the activation of A(1)R. Our results show that NECA binds to A(1)R in a similar mode to adenosine in the A(1)R crystal structure and NECA in the A(2A)R crystal structure. The A(1)R homodimer can be activated by one or two agonists with NECA occupying its orthosteric pockets in one (which we call the NECA-A(1)R system) or both protomers (which we call the dNECA-A(1)R system). In the NECA-A(1)R system, activation is predicated in the protomer without NECA bound. In the dNECA-A(1)R 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 A(1)R.