Abstract:
G-Protein Coupled Receptors (GPCRs) are the largest family of signaling pro teins and a better understanding of dynamics underlying functional mechanism is es sential in drug design. Although many studies have been performed to date, charac terizing conformational changes and dynamics in-between inactive and active states remains elusive. Here, the activation mechanism of Muscarinic acetylcholine receptor M2, which belongs to the GPCRs family and responsible from decreasing heart rate to normal rhythm by inhibiting cAMP (cyclic adenosine mono phosphate), has been explored by ANM-LD computational methodology that combines anisotropic network model (ANM) with all-atom Langevin dynamics (LD) simulations. The predicted phys ically plausible multiple conformational transition pathways from the inactive (3UON) towards the active states (4MQS, 4MQT) disclosed the dynamic determinants under lying the M2’s activation process. It was observed that certain collective ANM modes are essential for the activation and the hinge sites that coordinate the motion defined by these modes of motion aligns with the known functional important sites acting as molecular switches such as (DRY and NPxxY motifs, TM3-TM6 distance, salt bridge between R121 and E382). Furthermore, the two hydrophobic layers in TM domains dis play the coupling of the conformational changes with these switches and the continuous water pathway from extracellular side through intracellular side providing a continuous path from the ligand binding site to the G-protein binding site in the activation.
