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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 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的是引起蛋白质运动的分子细节，这些细节很难直接使用实验方法观察，但对于理解通道蛋白上的麻醉作用至关重要。我们将专注于被认为是通用麻醉剂的潜在靶标的NACHR。该研究的具体目的包括（a）在（？1）2？1？以及在没有麻醉药（控制系统）的3：1：1 popc：popa：popa：popa：popa：popa：胆固醇的3：1：1 popc：popa：popa：胆固醇（控制系统）中，神经元（？4）2（？2）3和（？7）5 NACHRS； （b）识别鱼雷（？1）2？1中的麻醉剂（卤代和异氟烷）相互作用位点？神经元（？4）2（？2）3和（？7）5 NACHR在开放通道状态下，通过执行灵活的配体对接并与我们自己的NMR数据进行比较，并与其他已发表的实验结果进行比较（例如，诱变和光疗法和光疗法标签）； （c）在存在对接麻醉药的情况下与（a）平行地重复MD模拟。该研究的假设：（1）麻醉药是两亲性的，与水孔中疏水性横梁附近的两个相邻的TM2亚基之间的界面特别相互作用，在EC-TM界面处的驱动点。 （2）麻醉剂在驱动点之一介导疏水性不匹配； （3）在扩展MD平衡后，将麻醉效应编码为第三和第四纪结构水平的全局变化； （4）与EC-TM界面的致动点的麻醉相互作用改变了TM2结构域的RMS波动，孔内疏水束的相互作用深远影响了疏水性侧链的重新定位和水通道的闪烁。