Inactive and active states and supramolecular organization of GPCRs: insights from computational modeling

Herein we make an overview of the results of our computational experiments aimed at gaining insight into the molecular mechanisms of GPCR functioning either in their normal conditions or when hit by gain-of-function or loss-of-function mutations. Molecular simulations of a number of GPCRs in their wild type and mutated as well as free and ligand-bound forms were instrumental in inferring the structural features, which differentiate the mutation- and ligand-induced active from the inactive states. These features essentially reside in the interaction pattern of the E/DRY arginine and in the degree of solvent exposure of selected cytosolic domains. Indeed, the active states differ from the inactive ones in the weakening of the interactions made by the highly conserved arginine and in the increase in solvent accessibility of the cytosolic interface between helices 3 and 6. Where possible, the structural hallmarks of the active and inactive receptor states are translated into molecular descriptors useful for in silico functional screening of novel receptor mutants or ligands. Computational modeling of the supramolecular organization of GPCRs and their intracellular partners is the current challenge toward a deep understanding of their functioning mechanisms.