Pentameric ligand-gated ion channels (pLGICs), embedded in the lipid membranes of nerve cells, mediate fast synaptic transmission and are major pharmaceutical targets. Because of their complexity and the limited knowledge of their structure, their working mechanisms have still to be fully unraveled at the molecular level. Over the past few years, evidence that the lipid membrane may modulate the function of membrane proteins, including pLGICs, has emerged. Here, we investigate, by means of molecular dynamics simulations, the behavior of the lipid membrane at the interface with the 5-HT${}_{3A}$ receptor (5-HT${}_{3A}$R), a representative pLGIC which is the target of nausea-suppressant drugs, in a nonconductive state. Three lipid compositions are studied, spanning different concentrations of the phospholipids, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine, and of cholesterol, hence a range of viscosities. A variety of lipid interactions and persistent binding events to different parts of the receptor are revealed in the investigated models, providing snapshots of the dynamical environment at the membrane-receptor interface. Some of these events result in lipid intercalation within the transmembrane domain, and others reach out to protein key sections for signal transmission and receptor activation, such as the Cys-loop and the M2-M3 loop. In particular, phospholipids, with their long hydrophobic tails, play an important role in these interactions, potentially providing a bridge between these two structures. A higher cholesterol content appears to promote lipid persistent binding to the receptor.

中文翻译：

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膜中的胆固醇含量促进了五聚体血清素门控离子通道中关键的脂蛋白相互作用

五聚体配体门控离子通道 (pLGIC) 嵌入神经细胞的脂质膜中，介导快速突触传递，是主要的药物靶点。由于它们的复杂性和对其结构的了解有限，它们的工作机制仍有待在分子水平上完全解开。在过去的几年中，已经出现了脂质膜可能调节膜蛋白（包括 pLGIC）功能的证据。在这里，我们通过分子动力学模拟研究了脂质膜在与 5-HT 的界面处的行为${}_{3\mathrm{一个}}$ 受体（5-HT${}_{3\mathrm{一个}}$R)，一种代表性的 pLGIC，它是恶心抑制药物的靶点，处于非导电状态。研究了三种脂质成分，涵盖不同浓度的磷脂、1-棕榈酰-2-油酰-sn-甘油-3-磷酸胆碱和 1-棕榈酰-2-油酰-sn-甘油-3-磷酸乙醇胺和胆固醇，因此具有一定的粘度范围。在研究的模型中揭示了与受体不同部分的各种脂质相互作用和持久结合事件，提供了膜受体界面动态环境的快照。这些事件中的一些导致跨膜结构域内的脂质嵌入，而其他事件涉及信号传输和受体激活的蛋白质关键部分，例如 Cys 环和 M2-M3 环。特别是，具有长疏水尾巴的磷脂在这些相互作用中发挥着重要作用，有可能在这两种结构之间架起一座桥梁。较高的胆固醇含量似乎促进脂质与受体的持久结合。