Cannabinoid receptor 2 (CBR2) is a class A G-protein coupled receptor (GPCR) that regulates the effects of endogenous cannabinoid signalling. Since CBR2 is mainly expressed in the immune tissues, it is associated with immunomodulatory roles in humans, which makes CBR2 an important target for inflammatory diseases. Although a number of experimentally resolved structures of human CBR2 have been reported in the protein data bank, they mostly feature stabilizing mutations and also exclude the extracellular and intracellular domains of the protein. Therefore, there is still a limited understanding on the structures, dynamics and ligand-interactions of CBR2. In this study, we attempt to fill this gap by building a complete, glycosylated atomistic models of CBR2 and exploring its conformational dynamics and ligand interactions using computational approaches. The missing segments of the known crystal structure of human CBR2 were constructed using threading-based molecular modelling approaches, and the glycosylation sites were attached with hybrid glycans to model the complete CBR2 model, which was then inserted within a lipid-bilayer. The conformational changes and interactions of membrane-embedded, glycosylated models of CBR2 were investigated using 1 ms long molecular dynamics (MD) simulation. The representative snapshots sampled through cluster analyses of MD trajectories were used to examine the binding mode and affinity of a select class of cannabinoid-based ligands. Our dynamic models reveal the most stable and flexible regions in CBR2 in response to glycosylation, and also highlight a possible correlation between the dynamics of the extracellular domains of CBR2 and its intracellular segments, mainly an intracellular loop that is linked with CBR2-G protein recognition processes. We also describe the key interactions of small molecule ligands and CBR2 at molecular level, which should provide some useful insights about this important GPCR target

Molecular dynamics and ligand interactions in human cannabinoid receptor 2

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.