Modeling the possible conformations of the extracellular loops in G-protein-coupled receptors.

This study presents the results of a de novo approach modeling possible conformational dynamics of the extracellular (EC) loops in G-protein-coupled receptors (GPCRs), specifically in bovine rhodopsin (bRh), squid rhodopsin (sRh), human beta-2 adrenergic receptor (beta2AR), turkey beta-1 adrenergic receptor (beta1AR), and human A2 adenosine receptor (A2AR). The approach deliberately sacrificed a detailed description of any particular 3D structure of the loops in GPCRs in favor of a less precise description of many possible structures. Despite this, the approach found ensembles of the low-energy conformers of the EC loops that contained structures close to the available X-ray snapshots. For the smaller EC1 and EC3 loops (6-11 residues), our results were comparable with the best recent results obtained by other authors using much more sophisticated techniques. For the larger EC2 loops (25-34 residues), our results consistently yielded structures significantly closer to the X-ray snapshots than the results of the other authors for loops of similar size. The results suggested possible large-scale movements of the EC loops in GPCRs that might determine their conformational dynamics. The approach was also validated by accurately reproducing the docking poses for low-molecular-weight ligands in beta2AR, beta1AR, and A2AR, demonstrating the possible influence of the conformations of the EC loops on the binding sites of ligands. The approach correctly predicted the system of disulfide bridges between the EC loops in A2AR and elucidated the probable pathways for forming this system.