Molecular modelling of cannabinoid CB1 receptor
Cannabinoid receptors are cell membrane receptors from the family of G protein-coupled receptors. Cannabinoid type 1 receptor (CB1R) is mostly expressed in the central nervous system. It is an attractive molecular target for the treatment of drug addiction, schizophrenia, bipolar disorder, motor dysfunction and metabolic syndrome. The cannabinoid receptor interacting protein 1a (CRIP1a) participates in regulation of CB1R activity. The EU-funded project CANNABIDIM was dedicated to modelling of CB1R. It aimed to investigate in silico the processes involved in homodimerisation of the CB1R and the interaction of the CB1R homodimer with ligands. Scientists also studied the effects of membrane cholesterol and CRIP1a on the functioning of the CB1R homodimer. First, homology models of CB1R in the active and inactive state and in complexes with the respective G proteins were constructed. Multiple parameters of the dimer interface, shape and electrostatic complementarity, and potential and free energy contributed to model construction. Simulations of molecular dynamics of dimers and monomers of CB1R in a lipid bilayer containing cholesterol allowed the team to decipher their functions. Next, constructed models of CRIP1a and CB1R-CRIP1a protein complex were used for molecular dynamics simulations. CRIP1a destabilised CB1R active conformation, possibly reducing the basal activity of the receptor, which was supported by the experimental data. The model showed that CRIP1a blocked CB1R interactions with Gi and Go proteins. Molecular dynamics studies investigated the assembly of CB1R monomers and CB1R-CRIP1a complexes in a lipid bilayer with and without cholesterol. The models showed that several transmembrane helices are involved in CB1R oligomerisation, which is in accordance with the experimental data. Cholesterol facilitated oligomerisation of the CB1R, acting as a glue at the oligomerisation interface. Understanding the mechanism of cannabinoid receptors' interactions is key to altering their functionality for therapeutic purposes.
Keywords
Molecular modelling, cannabinoid, CB1 receptor, homodimer, membrane cholesterol
