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.

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