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.

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