天然膜中烟碱型乙酰胆碱受体与脂质的自发结合
Spontaneous Lipid Binding to the Nicotinic Acetylcholine Receptor in a Native Membrane
摘要：
烟碱乙酰胆碱受体（nAChR）和其他五聚体配体门控离子通道（pLGIC）是天然的神经元膜与一个不寻常的脂质组成。虽然这是公认的，这些受体可以显着调制的脂质，基本机制已主要研究模型膜只有几个脂质种类。在这里，我们使用粗粒度的分子动力学（MD）模拟探测在一个复杂的准神经元膜的脂质的特异性结合。我们对由36种脂质组成的膜中的单个nAChR进行了总共50微秒的模拟。多种脂质物质之间的竞争产生复杂的分布。我们发现，总体而言，胆固醇选择凹intersubunit网站和PUFAs选择凸M4网站，而单不饱和和饱和脂质不富集在nAChR边界。为了表征结合到特定的网站，我们提出了一种新的方法来计算“密度阈值亲和力”从连续的密度分布。我们发现，M4的亲和力减弱与链刚性，这表明柔性链可能有助于放松圆锥形蛋白质形状造成的包装缺陷。对于任何位点，PE头基具有所有磷脂头基中最强的亲和力，但阴离子脂质仍如预期的那样产生对M4位点的中等高亲和力。我们观察到阴离子头基和饱和链之间的合作效应在M4网站的内部小叶。我们还分析了个别阴离子头基的亲和力。结合起来，这些见解可以调和几个明显矛盾的实验中的作用，阴离子磷脂调节nAChR。
英文摘要：
The nicotinic acetylcholine receptor (nAChR) and other pentameric ligand-gated ion channels (pLGICs) are native to neuronal membranes with an unusual lipid composition. While it is well-established that these receptors can be significantly modulated by lipids, the underlying mechanisms have been primarily studied in model membranes with only a few lipid species. Here we use coarse-grained molecular dynamics (MD) simulation to probe specific binding of lipids in a complex quasi-neuronal membrane. We ran a total of 50 microseconds of simulations of a single nAChR in a membrane composed of 36 species of lipids. Competition between multiple lipid species produces a complex distribution. We find that overall, cholesterol selects for concave intersubunit sites and PUFAs select for convex M4 sites, while monounsaturated and saturated lipids are unenriched in the nAChR boundary. In order to characterize binding to specific sites, we present a novel approach for calculating a "density-threshold affinity" from continuous density distributions. We find that affinity for M4 weakens with chain rigidity, which suggests flexible chains may help relax packing defects caused by the conical protein shape. For any site, PE headgroups have the strongest affinity of all phospholipid headgroups, but anionic lipids still yield moderately high affinities for the M4 sites as expected. We observe cooperative effects between anionic headgroups and saturated chains at the M4 site in the inner leaflet. We also analyze affinities for individual anionic headgroups. Combined, these insights may reconcile several apparently contradictory experiments on the role of anionic phospholipids in modulating nAChR.
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