Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1 Revealed by Microsecond-Level Molecular Dynamics Simulation
bioRxiv [Preprint]. 2024 Apr 20:2024.04.17.589939. doi: 10.1101/2024.04.17.589939.
ABSTRACT
The cannabinoid receptor CB1 is a G protein-coupled receptor that regulates critical physiological processes including pain, appetite, and cognition. Understanding the conformational dynamics of CB1 associated with transitions between inactive and active signaling states is imperative for developing targeted modulators. Using microsecond-level all-atom molecular dynamics simulations, we identified marked differences in the conformational ensembles of inactive and active CB1 states in apo conditions. The inactive state exhibited substantially increased structural heterogeneity and plasticity compared to the more rigidified active state in the absence of stabilizing ligands. Transmembrane helices TM3 and TM7 were identified as distinguishing factors modulating the state-dependent dynamics. TM7 displayed amplified fluctuations selectively in the inactive state simulations attributed to disruption of conserved electrostatic contacts anchoring it to surrounding helices in the active state. Additionally, we identified significant reorganization of key salt bridge and hydrogen bond networks known to control CB1 activation between states. For instance, a conserved D213-Y224 hydrogen bond and D184-K192 salt bridge interactions showed marked rearrangements between the states. Collectively, these findings reveal the specialized role of TM7 in directing state-dependent CB1 dynamics through electrostatic switch mechanisms. By elucidating the intrinsic enhanced flexibility of inactive CB1, this study provides valuable insights into the conformational landscape enabling functional transitions. Our perspective advances understanding of CB1 activation mechanisms and offers opportunities for structure-based drug discovery targeting the state-specific conformational dynamics of this receptor.
PMID:38659869 | PMC:PMC11042334 | DOI:10.1101/2024.04.17.589939