Understanding the Mechanism of Activation/Deactivation of GLP-1R via Accelerated Molecular Dynamics Simulation

Abstract

Glucagon-like peptide-1 receptor (GLP-1R), as a member of the class B G protein-coupled receptors (GPCRs), plays a crucial role in regulating blood glucose level signal recognition through its activation. The conformation changes during the activation pathway are of particular importance for its function. To investigate the activation mechanism of GLP-1R, the crystal structures of active and inactive forms are chosen to perform a total of 2 μs of accelerated molecular dynamics (aMD) simulations and 400 ns of conventional molecular dynamics (cMD) simulations. With the aid of structural analysis and potential of mean force (PMF) calculations, we reveal the role of different helices in the activation and deactivation process and obtain the intermediate states during activation and deactivation that are difficult to capture in experiments. Protein structure network (PSN) was utilised to clarify the allosteric communication pathways of activation and deactivation and reveal the mechanisms of its activation and deactivation. The results could advance our understanding of the activation mechanism of GLP-1R and the related drug design.