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Dynamic Spatiotemporal Determinants Modulate GPCR:G protein Coupling Promiscuity and Biased Signaling

Recent studies have shown that G protein coupled receptors (GPCRs) generally maintain a promiscuous coupling repertoire to different Ga protein families. This allows GPCRs to potentiate multiple cell signaling processes, but the mechanism behind how promiscuous GPCRs couple different G proteins remains unclear. Additionally, GPCRs have also been shown to signal through b‐arrestins and ligands have been designed to show “bias” in signaling towards b‐arrestins versus G proteins. I will demonstrate the importance of both the nature and lifetime of intermolecular contacts between GPCR and G protein or b‐arrestin in mediating the coupling strength as well as selective coupling among the G proteins or between G proteins and b‐arrestin. Using Molecular Dynamics simulations, we show the temporal persistence of GPCR:tranducer protein residue contacts at the interface play a critical role in selective, biased or promiscuous coupling of the transducer proteins. Our results show that promiscuous GPCRs gain the ability to promiscuously couple likely by shedding constraining contacts that confer selectivity observed among selective GPCRs. We have also used molecular dynamics simulations to identify the residues in the allosteric communication network from the extracellular region to the transducer coupling regions. This residue network shows conserved chemical properties across all class A GPCRs, demonstrating the importance of allosteric communication in modulating ligand bias.