TY - JOUR TI - Coarse-grained simulations of nicotinic acetylcholine receptors in complex mixed membranes DO - https://doi.org/doi:10.7282/T3222WWK PY - 2016 AB - Nicotinic acetylcholine receptors (nAChRs) are pentameric Ligand Gated Ion Channels that are critical to signaling across synapses and the neuromuscular junction; such signaling is facilitated by high densities of nAChRs in the post-synaptic membrane. Organization of nAChRs, including partitioning behavior in membranes containing dis- tinct lipid domains, is poorly characterized. Numerous experimental studies have shown nAChR gain-of-function likely caused by direct interactions with cholesterol, but a significant role for lipid domains has been suggested by nAChR gain-of-function upon bulk cholesterol depletion. Furthermore, the opportunity for cholesterol to have a direct interactions will likely have a complex dependence on the extent of domain formation and lipid species in the membrane, which has not been previously addressed. In the present research, we use Molecular Dynamics Simulations with coarse-grained resolution via the MARTINI model to investigate concentrations of cholesterol and other lipids local to nAChRs embedded in complex model membranes with a range of head groups and degrees of unsaturation. Cholesterol and unsaturated lipids are observed binding in deep non-annular sites in the nAChR bundle (based on the 2BG9 cryo-EM structure), consistent with our previous predictions. nAChR partitions, however, into cholesterol-poor phases, resulting in dynamic exchange between cholesterol and unsaturated phospholipids. KW - Computational and Integrative Biology KW - Lipids KW - Nicotinic receptors LA - eng ER -