Investigating allosteric effects on the functional dynamics of β2-adrenergic ternary complexes with enhanced-sampling simulations

-complexes with the β2-adrenergic receptor (ADRB2) in its apo-form and in the presence of four small ligands that exert different allosteric effects. Our results suggest that the structure and dynamics of arrestin-ADRB2 complexes depend strongly on the nature of the small ligands. The complexes exhibit a variety of different coupling orientations in terms of the depth of the finger loop in the receptor and activation states of ADRB2. The simulations also allow us to characterize the cooperativity between the ligand and intracellular binding partner (IBP). Based on the complete and consistent results, we propose an experimentally testable extended ternary complex model, where direction of the cooperative effect between ligand and IBP (positive or negative) and its magnitude are predicted to be a characteristic of the ligand signaling bias. This paves the avenue to the rational design of ligands with specific functional effects.