Interaction of Synthetic Cannabinoid Receptor Agonists with Cannabinoid Receptor I: Insights into Activation Molecular Mechanism.

Synthetic cannabinoid receptor agonists (SCRAs) have become a wide group of new psychoactive substances since the 2010s. For the last few years, the X-ray structures of the complexes of cannabinoid receptor I (CB) with SCRAs as well as the complexes of CB with its antagonist have been published. Based on those data, SCRA-CB interactions are analyzed in detail, using molecular modeling and molecular dynamics simulations. The molecular mechanism of the conformational transformation of the transmembrane domain of CB caused by its interaction with SCRA is studied. These conformational changes allosterically modulate the CB-G complex, providing activation of the G protein. Based on the X-ray-determined structures of the CB-ligand complexes, a stable apo conformation of inactive CB with a relatively low potential barrier of receptor activation was modeled. For that model, molecular dynamic simulations of SCRA binding to CB led to the active state of CB, which allowed us to explore the key features of this activation and the molecular mechanism of the receptor's structural transformation. The simulated CB activation is in accordance with the previously published experimental data for the activation at protein mutations or structural changes of ligands. The key feature of the suggested activation mechanism is the determination of the stiff core of the CB transmembrane domain and the statement that the entire conformational transformation of the receptor to the active state is caused by a shift of alpha helix TM7 relative to this core. The shift itself is caused by protein-ligand interactions. It was verified via steered molecular dynamics simulations of the X-ray-determined structures of the inactive receptor, which resulted in the active conformation of CB irrespective of the placement of agonist ligand in the receptor's active site.