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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们研究的最终目标是了解全身麻醉的分子机制。我们计算工作的直接目标是引出蛋白质运动的分子细节，这些细节很难通过实验方法直接观察，但对于理解通道蛋白的麻醉作用可能至关重要。我们将重点关注被认为是全身麻醉药潜在靶点的 nAChR。该研究的具体目标包括 (a) 对 (?1)2?1?? 的开放通道结构进行大规模 MD 模拟（根据需要 10 ns 或更长，使用不同种子重复 3 次）。以及神经元 (?4)2(?2)3 和 (?7)5 nAChR，在没有麻醉剂的情况下，由 3:1:1 POPC:POPA:胆固醇组成的完全水合膜贴片中（对照系统）； (b) 确定鱼雷 (?1)2?1?? 中麻醉剂（氟烷和异氟烷）相互作用位点通过进行灵活的配体对接并与我们自己的 NMR 数据和其他已发表的实验结果（例如诱变和光亲和力）进行比较，以及处于开放通道状态的神经元 (?4)2(?2)3 和 (?7)5 nAChR标签）； (c) 在对接麻醉剂存在的情况下重复与 (a) 平行的 MD 模拟。研究假设：（1）麻醉剂是两亲性的，与水孔疏水带附近的两个相邻TM2亚基之间的界面以及EC-TM界面的驱动点发生特异性相互作用； (2) 麻醉剂介导致动点之一的疏水性失配； (3) 麻醉效应在扩展 MD 平衡后被编码为三级和四级结构水平的全局变化； (4)麻醉剂与EC-TM界面驱动点的相互作用改变了TM2结构域的RMS波动，孔内疏水带的相互作用深刻影响疏水侧链的重新取向和水通道的闪烁。