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: 8364249
• 负责人: PEI TANG
• 金额: $ 0.11万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8364249
• 关键词: Affect; Anesthetics; Anions; Binding; Biomedical Research; Chemosensitization; Ensure; Funding; Gated Ion Channel; General Anesthesia; General anesthetic drugs; Goals; Grant; Halothane; High Performance Computing; Ion Channel; Ions; Ligands; Measurement; Molecular; Motion; Mutation; National Center for Research Resources; Neurons; Principal Investigator; Progress Reports; Proteins; Research; Research Infrastructure; Resources; Source; United States National Institutes of Health; Work; computer studies; cost; protein function; protein structure; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This renewal proposal seeks a continuing support from NCSA to ensure the progress of our on-going research funded by NIH (R01GM056257-11, R01GM66358-09, R37GM049202). The ultimate goal of our study is to understand the molecular mechanisms of general anesthesia through our combined experimental and computational efforts. Our immediate objective is to elucidate how general anesthetics interact with their putative targets and affect protein structures and motions. Our central hypothesis is that general anesthetics alter functions of these proteins by modulating functional relevant protein motions. As reflected in our research progress report in section III, we have worked on neuronal nAChRs and Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC) in the presence and absence of anesthetic halothane through MD simulations. Parallel to our computational studies, we have conducted many sets of structural and functional measurements on GLIC to determine where general anesthetics bind to GLIC and how they inhibit GLIC channel. We can turn GLIC into an anion channel through mutation at several critical residues and determine whether anesthetics inhibit or potentiate Cl? permeable GLIC (GLICCl). In this application, we have three aims. Aim 1 is to determine the important factors that can keep GLIC in an open-channel state during long MD simulations. Aim 2 is to correlate the redistribution of global dynamics profiles due to anesthetic binding with changes in channel conductance using long-timescale simulations. In Aim 3, we will determine the potential of mean force (PMF) for transporting a single Cl? ion along the GLIC channel and (B) determine the underlying cause of the experimentally observed potentiation or inhibition of GLIC channel by anesthetics. Collectively, we will integrate new experimental findings into our computational studies and reveal underlying mechanisms of anesthetic action on the pentameric ligand gated ion channels.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 此更新提案寻求 NCSA 的持续支持，以确保 NIH 资助的正在进行的研究取得进展（R01GM056257-11、R01GM66358-09、R37GM049202）。我们研究的最终目标是通过实验和计算的结合来了解全身麻醉的分子机制。我们的直接目标是阐明全身麻醉剂如何与其假定目标相互作用并影响蛋白质结构和运动。我们的中心假设是全身麻醉剂通过调节功能相关的蛋白质运动来改变这些蛋白质的功能。正如我们在第三节的研究进展报告中所反映的，我们通过 MD 模拟研究了存在和不存在麻醉氟烷的情况下的神经元 nAChR 和紫色地杆菌五聚体配体门控离子通道 (GLIC)。与我们的计算研究并行，我们对 GLIC 进行了多组结构和功能测量，以确定全身麻醉剂与 GLIC 结合的位置以及它们如何抑制 GLIC 通道。我们可以通过几个关键残基的突变将 GLIC 转变为阴离子通道，并确定麻醉剂是否抑制或增强 Cl？渗透性GLIC（GLICCl）。在此应用程序中，我们有三个目标。目标 1 是确定在长时间 MD 模拟期间可以使 GLIC 保持开放通道状态的重要因素。目标 2 是使用长时间尺度模拟将麻醉剂结合引起的全局动力学分布的重新分布与通道电导的变化关联起来。在目标 3 中，我们将确定传输单个 Cl 的平均力 (PMF) 的潜力。 (B) 确定实验观察到的麻醉剂对 GLIC 通道增强或抑制的根本原因。总的来说，我们将把新的实验结果整合到我们的计算研究中，并揭示五聚体配体门控离子通道麻醉作用的潜在机制。