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bioRxiv · 10.1101/2024.04.17.589939

Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1 Revealed by Microsecond-Level Molecular Dynamics Simulation

Isu, U. H.·Polasa, A.·Moradi, M.
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Abstract

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor (GPCR) that regulates critical physiological processes including pain, appetite, and cognition. Understanding the confor- mational 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 (MD) simulations, we identified marked differences in the conformational ensembles of inactive and active CB1 in apo. The inactive state exhibited substantially in- creased 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 reorganizations in key salt bridge and hydrogen bond networks con- tributing to the CB1 activation/inactivation. For instance, D213-Y224 hydrogen bond and D184-K192 salt bridge 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. Graphic for manuscript O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=174 SRC="FIGDIR/small/589939v2_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@ade7d7org.highwire.dtl.DTLVardef@1500e0corg.highwire.dtl.DTLVardef@ca4b04org.highwire.dtl.DTLVardef@10317eb_HPS_FORMAT_FIGEXP M_FIG For Table of Contents Only C_FIG

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Isu, U. H., Polasa, A., Moradi, M.. 2024-04-20. Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1 Revealed by Microsecond-Level Molecular Dynamics Simulation. https://doi.org/10.1101/2024.04.17.589939

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