title: Conformational changes in acetylcholine binding protein investigated by temperature accelerated molecular dynamics.
abstract: Despite the large number of studies available on nicotinic acetylcholine receptors, a complete account of the mechanistic aspects of their gating transition in response to ligand binding still remains elusive. As a first step toward dissecting the transition mechanism by accelerated sampling techniques, we study the ligand-induced conformational changes of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Temperature Accelerated Molecular Dynamics (TAMD) simulations we investigate the AChBP transition between the apo and the agonist-bound state. In long standard MD simulations, both conformations of the native protein are stable, while the agonist-bound structure evolves toward the apo one if the orientation of few key sidechains in the orthosteric cavity is modified. Conversely, TAMD simulations initiated from the native conformations are able to produce the spontaneous transition. With respect to the modified conformations, TAMD accelerates the transition by at least a factor 10. The analysis of some specific residue-residue interactions points out that the transition mechanism is based on the disruption/formation of few key hydrogen bonds. Finally, while early events of ligand dissociation are observed already in standard MD, TAMD accelerates the ligand detachment and, at the highest TAMD effective temperature, it is able to produce a complete dissociation path in one AChBP subunit.
authors.affiliation: School of Physics, University College Dublin, Dublin, Ireland.
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Mohammad Hosseini Naveh
authors.affiliation: Institut Pasteur and CNRS UMR 3528, Unité de Bioinformatique Structurale, Paris, France.
authors.forename: Therese E
authors.initials: TE
authors.lastname: Malliavin
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Maragliano
authors.affiliation: School of Physics, University College Dublin, Dublin, Ireland ; Department of Physics and Chemistry, University of Palermo, Palermo, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Cottone
authors.affiliation: School of Physics, University College Dublin, Dublin, Ireland ; Department of Physics, University of Roma "La Sapienza", Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciccotti
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D006860:Hydrogen Bonding; D008024:Ligands; D008120:Lobeline / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008974:Mollusca / Q000737:chemistry; D018722:Nicotinic Agonists / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry*; D013696:Temperature
chemical_list: C428944:AChBP protein, Lymnaea; D002352:Carrier Proteins; D008024:Ligands; D018722:Nicotinic Agonists; D021122:Protein Subunits; D008120:Lobeline