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.
Highlights
The transmembrane nicotinic acetylcholine receptors, belonging to the so-called ‘Cys-loop’ super-family of ligand-gated ion channels (LGICs) [1,2], are involved in a variety of biological processes [3,4,5] and have been implicated in the onset of Alzheimer’s disease [4,6] and nicotine addiction [7]
The nicotinic acetylcholine receptors (nAChRs) channel pore, located in the transmembrane domain (TMD), opens following the binding of agonist ligands in the orthosteric site located in the extracellular domain (ECD) of the protein
The ELIC structures showed the binding of anesthetics both in the TMD and in the ECD [23] and the binding of acetylcholine to the ECD [21]
Summary
The transmembrane nicotinic acetylcholine receptors (nAChRs), belonging to the so-called ‘Cys-loop’ super-family of ligand-gated ion channels (LGICs) [1,2], are involved in a variety of biological processes [3,4,5] and have been implicated in the onset of Alzheimer’s disease [4,6] and nicotine addiction [7]. The nAChR channel pore, located in the transmembrane domain (TMD), opens following the binding of agonist ligands in the orthosteric site located in the extracellular domain (ECD) of the protein. The structures of unliganded (apo) [26,27] and liganded (holo) state of AChBP [27,28,29,30,31,32,33,34,35,36,37,38,39,40] revealed how the ligands bind to the orthosteric pocket This pocket, present in each of the subunits, is lined by the so-called loop C and extends at the interface between subunits (Fig. 1). The AChBP structures revealed the influence of the ligand type on the degree of Cloop closure against the protein core [32], as the loop arrangements cluster into three groups: i) the antagonist-bound ‘‘open’’
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