Mechanism of Ligand Binding Pathways and Activation of the Succinate Receptor

Molecular dynamic (MD) simulations of high-resolution X-ray structures of GPR91 in the presence of free succinate molecules demonstrate that the acidic metabolite initially binds between TM6 and TM7 in the extracellular vestibule (ECV) before moving down through an intermediate stage to its final binding site between transmembrane helices. The low energy binding in the initial and the final binding stage with a higher energy barrier in the intermediate stage were investigated by well-tempered metadynamic.