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: 8171827
• 负责人: PEI TANG
• 金额: $ 0.15万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171827
• 关键词: Anesthetics; Computer Retrieval of Information on Scientific Projects Database; Etomidate; Funding; General Anesthesia; General anesthetic drugs; Global Change; Goals; Grant; Institution; Ion Channel; Knowledge; Mediating; Membrane; Methods; Molecular; Motion; Neuraxis; Propofol; Proteins; Research; Research Personnel; Resources; Simulate; Source; Structure; System; United States National Institutes of Health; base; insight; 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 potentially crucial to the understanding of anesthetic actions on the channel proteins. We will focus on GLIC whose channel function can be inhibited by general anesthetics. The specific aims for the study include (1) to perform a 100-ns or even longer MD simulation in a fully hydrated membrane patch in the absence of anesthetics (a control system); (2) to conduct parallel MD simulations in the presence of two clinically used anesthetics (propofol and etomidate); (3) to calculate PMFs of Na+ across the channel based on the structures generated in Aim 1 and 2. Hypotheses for the study: anesthetic interaction with the actuation points at the EC-TM interface and residues inside the channel will introduce significant changes in the structure and dynamics of GLIC. The anesthetic effects will be encoded as global changes at tertiary and quaternary structural level after extended MD simulations. The PMF calculations on these simulated structures in the absence and presence of anesthetics will offer valuable insights into how anesthetics mediate the function of GLIC channel. The knowledge acquired from the proposed study will be transferable for understanding anesthetic actions on other homologous channel proteins in the central nervous system.

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GLIC，其通道功能可被全身麻醉药抑制。该研究的具体目标包括（1）在没有麻醉剂（控制系统）的情况下，在完全水合的膜贴片中进行100纳秒甚至更长的MD模拟； (2) 在两种临床使用的麻醉剂（丙泊酚和依托咪酯）存在的情况下进行并行MD模拟； (3) 根据目标 1 和 2 中生成的结构计算跨通道的 Na+ PMF。研究假设：麻醉剂与 EC-TM 界面上的驱动点和通道内残留物的相互作用将导致 GLIC 的结构和动力学发生显着变化。经过扩展MD模拟后，麻醉效果将被编码为三级和四级结构水平的全局变化。在麻醉剂不存在和存在的情况下对这些模拟结构进行的 PMF 计算将为麻醉剂如何介导 GLIC 通道的功能提供有价值的见解。从拟议的研究中获得的知识将可用于理解中枢神经系统中其他同源通道蛋白的麻醉作用。