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Temperature Accelerated Molecular Dynamics investigation of conformational changes in acetylcholine binding protein: Simulation of AChBP

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 change of the acetylcholine binding protein (AChBP), a widely accepted model for the full receptor extracellular domain. Using unbiased Molecular Dynamics (MD) and Tem-perature 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.
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Submitted on : Tuesday, January 20, 2015 - 6:34:38 PM
Last modification on : Monday, January 13, 2020 - 5:08:16 PM
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Zeynab Hosseini, Thérèse E. Malliavin, Luca Maragliano, Grazia Cottone, Giovanni Ciccotti. Temperature Accelerated Molecular Dynamics investigation of conformational changes in acetylcholine binding protein: Simulation of AChBP. PLoS ONE, Public Library of Science, 2014, 9 (2), pp.e88555. ⟨10.1371/journal.pone.0088555⟩. ⟨pasteur-01107503⟩

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