Computational study of selectivity, gating and mutation in the acetylcholine receptor and potassium channels

乙酰胆碱受体和钾通道的选择性、门控和突变的计算研究

• 批准号: nhmrc : 458589
• 负责人: A/Pr Ben Corry
• 金额: $ 20.1万
• 依托单位: The University of Western Australia
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/computational-study-selectivity-potassium-channels/82425
• 关键词: Computational; study; selectivity; gating; mutation

One way cells in living organisms communicate with each other is via the passage of charged particles across the cell membrane. This takes place through ion channels, large protein molecules that span the membrane and allow small molecules or ions to pass through a central pore. Malfunction of ion channels is known to underlie a variety of disorders including epilepsy, hypertension, kidney disease, heart attack, deafness. Channels also provide promising targets for making new broad spectrum antibiotics and antivirals. This project aims to study two important types of ion channel: acetylcholine receptors that convey signals between nerve and muscle cells, and potassium channels that regulate the nerve impulses themselves. The binding of the neurotransmitter acetylcholine released from a nerve cell to acetylcholine receptors in the muscle cell prompts the opening of a cation conductive pore. The resulting influx of ions initiates a cascade of events ending in the contraction of the muscle fibre. However, the way in which this channel opening is initiated and how ions move into the muscle cell remain to be determined. Potassium channels are primarily used to rapidly 'switch off' nerve impulses so that subsequent messages can be passed through the nerve cell. To do this they have to be highly discriminatory, allowing only potassium to pass across the cell membrane and not sodium that would initiate another impulse. Although we now know what these tiny proteins look like, it is not clear how they differentiate between types of ions while still allowing many millions to pass each second. We will use computer simulations to study how these two type of channel open and close, and how they discriminate between different ion types. Using sophisticated computational techniques on Australia's most powerful supercomputers we aim to elucidate this fundamental area of human biology in the hope of deriving treatments for some debilitating neuromuscular diseases.

生物体中的细胞相互交流的一种方式是通过带电粒子穿过细胞膜。这是通过离子通道发生的，离子通道是跨越膜的大蛋白分子，允许小分子或离子通过中心孔。已知离子通道的功能障碍是多种疾病的基础，包括癫痫、高血压、肾病、心脏病发作、耳聋。通道还为制备新的广谱抗生素和抗病毒药提供了有希望的靶点。该项目旨在研究两种重要类型的离子通道：在神经和肌肉细胞之间传递信号的乙酰胆碱受体，以及调节神经冲动本身的钾通道。从神经细胞释放的神经递质乙酰胆碱与肌肉细胞中的乙酰胆碱受体的结合促使阳离子传导孔的打开。由此产生的离子流入引发了一系列事件，最终导致肌肉纤维收缩。然而，这种通道开放的方式以及离子如何进入肌肉细胞仍有待确定。钾离子通道主要用于快速“关闭”神经冲动，以便随后的信息可以通过神经细胞传递。要做到这一点，它们必须具有高度的辨别力，只允许钾离子穿过细胞膜，而不允许钠离子穿过细胞膜，因为钠离子会引发另一个冲动。虽然我们现在知道这些微小的蛋白质看起来像什么，但尚不清楚它们如何区分不同类型的离子，同时每秒仍允许数百万个离子通过。我们将使用计算机模拟来研究这两种类型的通道如何打开和关闭，以及它们如何区分不同的离子类型。我们在澳大利亚最强大的超级计算机上使用复杂的计算技术，旨在阐明人类生物学的这一基本领域，以期为一些使人衰弱的神经肌肉疾病提供治疗。