Abstract
G-protein-coupled receptors (GPCRs) are transmembrane receptors involved in diverse biological functions. Despite the diversity in their amino acid sequences, class A GPCRs exhibit a conserved structural topology and possibly a common mechanism of receptor activation. To understand how this high sequence diversity translates to a conserved functional mechanism, we have compared the dynamic behavior of eight class A GPCRs comprised of six biogenic amine receptors, adenosine A(2A), and the peptide receptor protease-activated receptor 1. Starting from the crystal structures of the inactive state of these receptors bound to inverse agonists or antagonists, we have performed multiple all-atom MD simulations adding up to several microseconds of simulation. We elucidated the similarities and differences in the dynamic behavior and the conformational ensembles sampled by these eight class A GPCRs. Among the six biogenic amine receptors studied here, β(2)-adrenergic receptor shows the highest level of fluctuation in the sixth and seventh transmembrane helices, possibly explaining its high basal activity. In contrast, the muscarinic acetylcholine receptors show the lowest fluctuations as well as tight packing and low hydration of the transmembrane domain. All eight GPCRs show several conserved allosteric communication pipelines from the residues in the agonist binding site with the G-protein interface. Positions of the residues along these pipelines that serve as major hubs of allosteric communication are conserved in their respective structures. These findings have important implications in understanding the dynamics and allosteric mechanism of communication in class A GPCRs and hence are useful for designing conformation-specific drugs.