Eur Biophys J (2009) 38:961–970 DOI 10.1007/s00249-009-0476-3 123 ORIGINAL PAPER Computational study of the transmembrane domain of the acetylcholine receptor Chen Song · Ben Corry Received: 24 December 2008 / Revised: 1 May 2009 / Accepted: 4 May 2009 / Published online: 23 May 2009  European Biophysical Societies’ Association 2009 Abstract The nicotinic acetylcholine receptor (nAChR) is a ligand-gated ion channel protein whose transmembrane domain (TM-domain) is believed to be responsible for channel gating via a hydrophobic eVect. In this work, we perform molecular dynamics and Brownian dynamics sim- ulations to investigate the eVect of transmembrane potential on the conformation and water occupancy of TM-domain, and the resulting ion permeation events. The results show that the behavior of the hydrophobic gate is voltage-depen- dent. Large hyperpolarized membrane potential can change the conformation of TM-domain and water occupancy in this region, which may enable ion conduction. An electrostatic gating mechanism is also proposed from our simulations, which seems to play a role in addition to the well-known hydrophobic eVect. Keywords Ion channel · Acetylcholine receptor · Gating · Membrane potential · Molecular dynamics · Brownian dynamics Introduction The nicotinic acetylcholine receptor (nAChR) belongs to the “Cys-loop” family of ligand-gated ion channels that mediate synaptic neurotransmission (Sine and Engel 2006). The nAChR is of crucial physiological importance and its malfunction is related to a number of known diseases including epilepsy, congenital myasthenia, and muscle weakness (Ashcroft 2006). However, although the genetics, kinetics, electrophysiology, and many topological aspects have been well characterized for the nAChR (Barry and Lynch 2005; Jordan 2005), an atomic-scale understanding of the protein was not available until the development of recent models based on 4-Å-resolution maps obtained from cryo-electron microscopy (Miyazawa et al. 2003; Unwin 2005). The channel is made up of Wve homologous subunits packed around a central pore, forming a structure with Wve- fold pseudosymmetry. It is divided into three domains, including the transmembrane domain (TM-domain), which is embedded in the lipid as shown in Fig. 1 and is believed to be responsible for the gating behavior. Since the appearance of experimentally based models of the Torpedo nAChR (Miyazawa et al. 2003; Unwin 2005), much theoretical research has taken place to study where and how the gating mechanism happens in the TM-domain (Cheng et al. 2006; Corry 2004, 2006; Law et al. 2005; Taly et al. 2005). While there has been some suggestion that the channel gate is located at the intracellular end of the TM-domain at the location of a number of charged or polar residues (Pascual and Karlin 1998; Wilson and Karlin 1998), a more common view is developing that the gate is midway across the membrane. Here there are a number of hydrophobic residues that may act to block ion permeation using a so-called hydrophobic gating mechanism by which a closed-state pore is not necessary physically blocked, and a small radius change can dramatically improve the water occupancy, which may lead to ion conduction (Beckstein et al. 2003; Beckstein and Sansom 2006; Corry 2006; Cymes and Grosman 2008). As yet, this has not been shown to occur in the more recent reWned structure of nAChR (Unwin 2005). However, the gating mechanism is still not clear due to the lack of dynamic gating details and C. Song (&) · B. Corry School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Crawley, WA 6009, Australia e-mail: sc3210@gmail.com