Molecular simulations reveal the impact of RAMP1 on ligand binding and dynamics of CGRPR heterodimer

Abstract

ABSTRACTThe release of the neuropeptide of calcitonin gene-related peptide (CGRP) plays a key role in the mechanisms of migraine pathology and pain perception as it causes vasodilatation, neurogenic inflammation, mast cell degranulation, sensory signal activation and peripheral sensitivity. Although the findings on the effectiveness of CGRP-targeted therapies in migraine provide new information about the pathophysiology of migraine, questions remain on how the CGRP mechanisms fit into the overall migraine theory. The cryo-EM structure of Gs-protein complexed human CGRP receptor (CGRPR) with bound endogenous CGRP neuropeptide paved the way of understanding the insights into the CGRP receptor function. With several molecular modeling approaches, molecular dynamics (MD) simulations and post-MD analyzes, we aimed to investigate the importance of RAMP1 in the stability of calcitonin receptor-like receptor (CLR). Moreover, we compared the binding modes of the CGRP neuropeptide and CGRPR antagonists (i.e., telcagepant and rimegepant) within the presence or absence of RAMP1. We also investigated the global and local effects of bound molecules on CGRPR as well as their effects on the CLR-RAMP1 interaction interfaces. Results showed that although these molecules stay stable at the ectodomain binding site, they can also bind to the orthosteric ligand binding pocket and form the crucial interactions occurred in the CGRP agonism, which may be interpreted as non-specificity of the ligands, however, most of these interactions at orthosteric site are not sustainable or weak. Particularly, RAMP1 may also be important for the stability of TM domain of CLR hereby stabilizing the orthosteric binding pocket.