Structure-based simulations reveal concerted dynamics of GPCR activation

G protein-coupled receptors (GPCRs) are a vital class of proteins that transduce biological signals across the cell membrane. However, their allosteric activation mechanism is not fully understood; crystal structures of active and inactive receptors have been reported, but the functional pathway between these two states remains elusive. Here, we use structure-based (Gō-like) models to simulate activation of two GPCRs, rhodopsin and the β₂ adrenergic receptor (β₂AR). We used data-derived reaction coordinates that capture the activation mechanism for both proteins, showing that activation proceeds through quantitatively different paths in the two systems. Both reaction coordinates are determined from the dominant concerted motions in the simulations so the technique is broadly applicable. There were two surprising results. First, the main structural changes in the simulations were distributed throughout the transmembrane bundle, and not localized to the obvious areas of interest, such as the intracellular portion of Helix 6. Second, the activation (and deactivation) paths were distinctly nonmonotonic, populating states that were not simply interpolations between the inactive and active structures. These transitions also suggest a functional explanation for β₂AR's basal activity: it can proceed through a more broadly defined path during the observed transitions.