LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS

离子通道麻醉效果的大规模 MD 模拟

• 批准号: 7956089
• 负责人: PEI TANG
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956089
• 关键词: Affect; Anesthetics; Biomedical Research; Cholesterol; Computer Retrieval of Information on Scientific Projects Database; Data; Docking; Funding; General Anesthesia; General anesthetic drugs; Global Change; Goals; Grant; Halothane; High Performance Computing; Hydrophobicity; Institution; Ion Channel; Isoflurane; Ligands; Mediating; Membrane; Methods; Molecular; Motion; Mutagenesis; Neurons; Photoaffinity Labels; Proteins; Publishing; Research; Research Personnel; Resources; Seeds; Side; Site; Source; Structure; System; Torpedo; United States National Institutes of Health; Water; aqueous; flexibility; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ultimate goal of our study is to understand the molecular mechanisms of general anesthesia. The immediate objective of our computational efforts is to elicit the molecular details of protein motions that are difficult to observe directly with experimental methods but are potentially crucial to the understanding of anesthetic actions on the channel proteins. We will focus on nAChRs that have been suggested to be potential targets for general anesthetics. The specific aims for the study include (a) to perform large-scale MD simulations (10 ns or longer as needed, 3 repeats with different seeds) on open-channel structures of the (?1)2?1?? and the neuronal (?4)2(?2)3 and (?7)5 nAChRs in a fully hydrated membrane patch of 3:1:1 POPC:POPA:Cholesterol in the absence of anesthetics (control systems); (b) to identify anesthetic (halothane and isoflurane) interaction sites in the Torpedo (?1)2?1?? and the neuronal (?4)2(?2)3 and (?7)5 nAChRs in the open-channel state by performing flexible ligand docking and comparing with our own NMR data and with other published experimental results (e.g., mutagenesis and photoaffinity labeling); and (c) To repeat MD simulations parallel to (a) in the presence of the docked anesthetics. Hypotheses for the study: (1) anesthetics, being amphipathic, interact specifically with the interface between two adjacent TM2 subunits near the hydrophobic girdle in the aqueous pore and at the actuation points at EC-TM interface; (2) anesthetics mediate the hydrophobicity mismatch at one of the actuation points; (3) anesthetic effects are encoded as global changes at tertiary and quaternary structural level after extended MD equilibration; (4) anesthetic interaction with the actuation points at EC-TM interface alters the RMS fluctuation of the TM2 domains, and the interaction at the hydrophobic girdle within the pore profoundly affects the re-orientation of the hydrophobic side chains and the flickering of water passage.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的最终目的是了解全身麻醉的分子机制。我们计算工作的直接目标是得出蛋白质运动的分子细节，这些细节很难用实验方法直接观察到，但对理解麻醉对通道蛋白质的作用可能是至关重要的。我们将重点介绍已被认为是全麻药潜在靶点的nAChRs。研究的具体目标包括：(A)对(？1)2？1？？在无麻醉剂(对照系统)的情况下，在3：1：1POPC：POPA：胆固醇的全水合膜片中检测神经元(？4)2(？2)3和(？7)5nAChRs；通过与我们自己的核磁共振数据和其他已发表的实验结果(如突变和光亲和标记)进行灵活的配基对接，并与开放通道状态下的神经元(？4)2(？2)3和(？7)5nAChRs进行比较；以及(C)在对接的麻醉药存在的情况下重复与(A)平行的MD模拟。本研究的假设是：(1)麻醉药是两亲性的，它与相邻的两个TM2亚基之间的界面以及EC-TM界面上的激活点发生了特异性的相互作用；(2)麻醉剂调节了其中一个激活点的疏水性失配；(3)麻醉效应被编码为延长MD平衡后三、四级结构水平上的整体变化；(4)麻醉剂与EC-TM界面激活点的相互作用改变了TM2结构域的均方根起伏，而孔内疏水带处的相互作用深刻地影响了疏水侧链的重新定位和水路的闪烁。