title: A Structural Model of the Human α7 Nicotinic Receptor in an Open Conformation.
abstract: Nicotinic acetylcholine receptors (nAchRs) are ligand-gated ion channels that regulate chemical transmission at the neuromuscular junction. Structural information is available at low resolution from open and closed forms of an eukaryotic receptor, and at high resolution from other members of the same structural family, two prokaryotic orthologs and an eukaryotic GluCl channel. Structures of human channels however are still lacking. Homology modeling and Molecular Dynamics simulations are valuable tools to predict structures of unknown proteins, however, for the case of human nAchRs, they have been unsuccessful in providing a stable open structure so far. This is due to different problems with the template structures: on one side the homology with prokaryotic species is too low, while on the other the open eukaryotic GluCl proved itself unstable in several MD studies and collapsed to a dehydrated, non-conductive conformation, even when bound to an agonist. Aim of this work is to obtain, by a mixing of state-of-the-art homology and simulation techniques, a plausible prediction of the structure (still unknown) of the open state of human α7 nAChR complexed with epibatidine, from which it is possible to start structural and functional test studies. To prevent channel closure we employ a restraint that keeps the transmembrane pore open, and obtain in this way a stable, hydrated conformation. To further validate this conformation, we run four long, unbiased simulations starting from configurations chosen at random along the restrained trajectory. The channel remains stable and hydrated over the whole runs. This allows to assess the stability of the putative open conformation over a cumulative time of 1 μs, 800 ns of which are of unbiased simulation. Mostly based on the analysis of pore hydration and size, we suggest that the obtained structure has reasonable chances to be (at least one of the possible) structures of the channel in the open conformation.
authors.affiliation: Center for Life Nano Science @Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Chiodo
authors.affiliation: Institut Pasteur and CNRS UMR 3528, Unité de Bioinformatique Structurale, Paris, France.
authors.forename: Thérèse E
authors.initials: TE
authors.lastname: Malliavin
authors.affiliation: Center for Synaptic Neuroscience, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Maragliano
authors.affiliation: Department of Physics and Chemistry, University of Palermo, Palermo, Italy; School of Physics, University College Dublin, Dublin, Ireland.
authors.forename: Grazia
authors.initials: G
authors.lastname: Cottone
authors.affiliation: Department of Physics, University of Roma "La Sapienza", Rome, Italy; School of Physics, University College Dublin, Dublin, Ireland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciccotti
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011487:Protein Conformation; D055503:Protein Multimerization; D016415:Sequence Alignment; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor