Delineating the conformational landscape of cannabinoid receptor 1 (CB1R) using gaussian accelerated molecular dynamics and network analysis.

Abstract

The cannabinoid receptor 1, CB1R, is a class A GPCR implicated in various disease states, including pain and inflammation. Interestingly, both the agonists, which can alleviate pain, and the antagonists, which can lead to appetite suppression in obese patients, have substantial therapeutic benefits. Crystal structures for the CB1R have also been determined in the inactive and active states. However, the role of these ligands in stabilizing these different states and how they contribute to this shift in equilibria is relatively unknown. The free energy surface for these transitions has also not been determined. Using Gaussian Accelerated MD, we have explored the different conformational states of the CB1R, exploring both the effects of orthosteric and allosteric ligands on the free energy landscape. Furthermore, we have analyzed the residue contacts and performed network analysis to determine the information flow pertinent to the transition between states. The results provide unprecedented insights into the activation of CB1R, and the critical residues involved in this process. These results can help to guide structure-based drug design where potential drugs can be evaluated on their ability to stabilize a preferred conformation of the receptor of focus.