Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling

The α7 nicotinic acetylcholine receptor plays a central role in higher brain functions and is implicated in many neurological disorders. Yet, the therapeutic potential of nicotinic agonists targeting α7 has been limited by the so-called “desensitization” of the activation response. Using high-resolution structures augmented by MD simulations and Markov-state modeling, we shed light onto the mechanism of receptor desensitization by the discovery of a new open-channel intermediate between the active and desensitized states. We have shown that this state accounts for the paradoxical phenotype of α7 constitutive mutants and suggests a novel mode of action for allosteric ligands. As a complement to the Science presented in the corresponding manuscript, here we provide: PDB coordinates of the D-open and D-closed conformational states of α7-nAChR extracted from MD simulations and Markov-state modeling (basins 1-4 of the MSM of the desensitized state). Jupyter Notebook and input data to construct the MSM of the desensitized state of α7-nAChR. Gromacs files: initial coordinates, topology and parameters files for running MD simulations of α7-nAChR wild-type, L247T mutant, and wild-type in complex with PAMs. A video (MP4) representing the conformational transition between D-open and D-closed along the minimum free-energy pathway.