Logo of Science Foundation Ireland  Logo of the Higher Education Authority, Ireland7 CapacitiesGPGPU Research Projects
Ireland's High-Performance Computing Centre | ICHEC
Home | News | Infrastructure | Outreach | Services | Research | Support | Education & Training | Consultancy | About Us | Login


Title:Conformational Changes in Acetylcholine Binding Protein Investigated by Temperature Accelerated Molecular Dynamics
Authors:Zeynab Mohammad Hosseini Naveh, Therese E. Malliavin, Luca Maragliano, Grazia Cottone, Giovanni Ciccotti, 2014
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.
ICHEC Project:Large Scale Conformational Transitions In Ligand Gated Ion Channels
Publication:Mohammad Hosseini Naveh Z, Malliavin TE, Maragliano L, Cottone G, Ciccotti G (2014) Conformational Changes in Acetylcholine Binding Protein Investigated by Temperature Accelerated Molecular Dynamics. PLoS ONE 9(2): e88555. doi:10.1371/journal.pone.0088555
URL: http://dx.doi.org/10.1371/journal.pone.0088555
Keywords: Acetylcholine; Biochemical simulations; Crystal structure; Free energy; Hydrogen bonding; Nicotinic acetylcholine receptors; Protein structure; X-ray crystallography
Status: Published

return to publications list