Unraveling how Lipophilic Modulators Alter pLGIC Function via Interactions with the M4 Transmembrane Helix

揭示亲脂性调节剂如何通过与 M4 跨膜螺旋相互作用改变 pLGIC 功能

• 批准号: 10785755
• 负责人: Mark Joseph Arcario
• 金额: $ 18.56万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10785755
• 关键词: Address; Advisory Committees; Affect; Affinity; Anesthesia procedures; Anesthesiology; Anesthetics; Award; Binding; Binding Sites; Biophysics; Characteristics; Computational Technique; Contracts; Critical Care; Cryoelectron Microscopy; Data; Dementia; Development; Docosahexaenoic Acids; Drug Design; Electrophysiology (science); Elements; Equilibrium; Erwinia; Essential Drugs; Family; Fatty Acids; Fluorescent Probes; Free Energy; Goals; Grain; Human; Intelligence; Ion Channel; Ion Channel Gating; Ions; Knowledge; Ligands; Lipid Binding; Lipids; Medicine; Membrane; Membrane Proteins; Mentors; Methods; Modeling; Modernization; Molecular; Molecular Conformation; Movement; Nervous System; Neuromuscular Blocking Agents; Neuromuscular Diseases; Nicotinic Receptors; Outcome; Pharmaceutical Preparations; Pharmacology; Phospholipids; Physicians; Physiological; Polyunsaturated Fatty Acids; Proteins; Publishing; Research; Rest; Scientist; Site; Structure; Synaptic Transmission; System; Techniques; Testing; Thermodynamics; Transmembrane Domain; Universities; Washington; Work; addiction; alpha-bungarotoxin receptor; career; career development; chronic pain management; computer studies; desensitization; design; drug development; drug discovery; innovation; insight; interest; lipophilicity; member; method development; molecular dynamics; molecular modeling; neurosteroids; new therapeutic target; novel; novel therapeutics; protein function; protein structure; rational design; research and development; simulation; skills; structural determinants; supportive environment

Project Summary/Abstract Dr. Mark Arcario is a cardiothoracic anesthesiologist whose long-term goal is to be an independent physician- scientist studying molecular mechanisms of allostery in ion channels. His research background is in computational biophysics of membrane proteins with a focus on the effects of lipids and lipophiles on membrane protein structure and function. He has a special interest in pentameric ligand-gated ion channels (pLGICs) and mechanisms of anesthetic action. Several endogenous lipids, including neurosteroids, phospholipids, and fatty acids, are strong allosteric modulators of pLGICs and it has been suggested that drugs, including anesthetics, exploit these innate regulatory mechanisms. It is not well-known how lipophiles, which bind at the periphery of the protein, alter channel function and equilibrium between functional states. Such a molecular mechanism is essential for the rational, structure-based design of new drugs targeting this family of channels. To address this knowledge gap, the candidate will use a combination of innovative molecular dynamics (MD) techniques to characterize state-dependent structural ensembles of prokaryotic pLGIC, ELIC (Erwinia ligand-gated ion channel), and the human 7 nicotinic acetylcholine receptor (nAChR). Aim 1 will determine how the conformation of the lipid-facing, fourth transmembrane (M4) helix varies with the functional state of the channel (i.e., resting, activated, desensitized), using computational electrophysiology methods. Aim 2 will characterize the binding site of docosahexaenoic acid (DHA), a polyunsaturated fatty acid, and how binding of DHA causes inhibition using multiscale simulation and free energy calculations. This work will yield novel insight into state-dependent dynamics of pLGICs as well as establish a molecular model of lipophilic allosteric modulation. This research will be conducted under Dr. Wayland Cheng, an expert in pLGIC structure and function with a focus on lipid binding and modulation, along with co-mentor, Dr. Grace Brannigan, an expert in computational biophysics with a focus on MD method development and application to membrane proteins. An advisory committee comprised of Dr. Alex Evers, an expert in anesthetic pharmacology, Dr. Baron Chanda, an expert in ion channel thermodynamics and gating, and Dr. Jerome Hénin, an expert in free energy calculations, will aid in the scientific development of the candidate. The research plan will allow the candidate to develop skills in free energy calculations and computational electrophysiology, which will prepare him for a career in computational biophysics of ion channels. In addition, involvement in career development activities during this award will prepare the candidate for independence by the end of the award. The Department of Anesthesiology at Washington University in St. Louis, a leader in academic anesthesiology, provides an excellent and supportive environment for ion channel research and development of physician-scientists.

项目概要/摘要 Mark Arcario 博士是一名心胸麻醉师，其长期目标是成为一名独立医生- 研究离子通道变构分子机制的科学家，他的研究背景是在。 膜蛋白的计算生物物理学，重点关注脂质和亲脂剂对膜的影响 他对五聚体配体门控离子通道（pLGIC）和蛋白质结构和功能特别感兴趣。 几种内源性脂质的麻醉作用机制，包括神经类固醇、磷脂和脂肪。 酸是 pLGIC 的强变构调节剂，并且有人建议药物，包括麻醉剂， 目前尚不清楚亲脂性物质如何利用这些先天调节机制。 蛋白质，改变通道功能和功能状态之间的平衡。 对于针对该通道家族的新药物的合理、基于结构的设计至关重要。 知识差距，候选人将结合使用创新的分子动力学（MD）技术来 表征原核 pLGIC、ELIC（欧文氏菌配体门控离子）的状态依赖性结构整体 通道），而人类 α7 烟碱乙酰胆碱受体 (nAChR) 将决定如何构象。 面向脂质的第四跨膜 (M4) 螺旋的变化随通道的功能状态（即静息、 激活，脱敏），使用计算电生理学方法来表征结合位点。 二十二碳六烯酸 (DHA)（一种多不饱和脂肪酸）的作用，以及 DHA 的结合如何引起抑制 这项工作将产生对状态相关的新见解。 本研究将研究 pLGIC 的动力学并建立亲脂性变构调节的分子模型。 由 Wayland Cheng 博士指导，他是 pLGIC 结构和功能方面的专家，重点是脂质结合 和调制，以及共同导师，计算生物物理学专家 Grace Brannigan 博士，重点关注 MD 方法开发和膜蛋白应用咨询委员会由 Dr. Alex Evers，麻醉药理学专家，Baron Chanda 博士，离子通道热力学专家 和门控，以及自由能计算专家 Jerome Hénin 博士将帮助科学发展 该研究计划将使候选人能够发展自由能计算和计算方面的技能。 计算电生理学，这将为他从事离子通道计算生物物理学的职业生涯做好准备。 此外，在获奖期间参与职业发展活动将为候选人做好准备 圣路易斯华盛顿大学麻醉学系于获奖结束时获得独立， 学术麻醉学领域的领导者，为离子通道研究提供了良好的支持性环境 和医师科学家的发展。