How intrinsic dynamics and allostery in G-protein coupled receptors (GPCR) define functional selectivity?

G-protein Coupled Receptors (GPCRs) are the largest family of the of sensory proteins which play an important role in many diseases related to signaling pathways. Thus, understanding GPCR activation mechanism is a corner stone in drug development. However, the transition pathways between inactive/active states remains not fully explored. In this thesis, a new approach, ANM-LD methodology, that combines the Anisotropic Network Model (ANM) and Langevin Dynamics (LD) is performed to decipher the transition pathways in the activation process and determine the key dynamic factors underlying the conformational changes of GPCR family. Towards this goal, three different receptor families (M2R, ß2AR, and NTSR1) are studied. The predicted transition pathways reveal that the intrinsic dynamic modes of the inactive state enable the conformational changes essential for the activation. As a result, the distances between TM3-TM6 and TM3-TM7 helices and the path of some functionally important motifs describe the major pathway that show commonality and differences in all three GPCRs. The agonist binding pocket interactions differ markedly for different subspecies, which are reflected in the selected dynamic modes of motion. When M2R is compared with NTSR1 and ß2AR, the weaker packing interactions result in more flexible segments in the connector of NTSR1 and ß2AR resulting in the TM3-TM6 distance to decay slower. Although a common agonist binding site does not exist, the conserved DRY, and NPxxY motifs are the common drivers of the GP binding site.The hinges of the most dominant dynamic modes coincide functionally important residues, constitute the dynamic infrastructure of allosteric interactions and enables the communication between the extracellular and intracellular sides of the structure.