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.

项目摘要/摘要 马克·阿卡里奥（Mark Arcario）博士是一名心胸麻醉师，其长期目标是成为独立的医生 - 科学家研究了离子通道中变构的分子机制。他的研究背景是 膜蛋白的计算生物物理学，侧重于脂质和脂肪对膜的影响 蛋白质结构和功能。他对五聚合配方门控离子通道（PLGICS）和 麻醉作用的机制。几种内源性脂质，包括神经蛋白酶，磷脂和脂肪 酸是PLGICS强的变构调节剂，有人提出包括麻醉药，包括麻醉药的药物 利用这些先天的监管机制。它不是众所周知的脂肪寄生者，它如何在外围结合 蛋白质，改变通道功能和功能状态之间的等效。这样的分子机制是 针对针对该渠道家族的新药的理性，基于结构的设计至关重要的。解决这个问题 知识差距，候选人将使用创新分子动力学（MD）技术的组合 表征核plgic的状态依赖性结构集合（Erwinia配体离子离子） 通道）和人类7烟碱乙酰胆碱受体（NACHR）。 AIM 1将决定如何构象 面向脂质的，第四跨膜（M4）螺旋螺旋的品种，具有通道的功能状态（即静止， 使用计算电生理方法激活，脱敏）。 AIM 2将表征绑定位点 Docosahexaenoic酸（DHA），一种多不饱和脂肪酸，以及DHA的结合如何引起抑制 多尺度模拟和自由能计算。这项工作将产生对国家依赖性的新颖洞察力 PLGICS的动力学以及建立亲脂性变构调制的分子模型。这项研究会 在PLGIC结构和功能专家Wayland Cheng博士下进行，重点是脂质结合 和调制，并与副恩格·布兰尼根（Grace Brannigan）博士一起，他是计算生物物理学专家，重点 关于MD方法开发和应用于膜蛋白的应用。咨询委员会完成了博士 Alex Evers，麻醉药理学专家，Chanda博士，离子频道热力学专家Baron Chanda博士 和门控，自由能量计算专家JeromeHénin博士将有助于科学发展 候选人。该研究计划将使候选人能够发展自由能计算的技能，并 计算电生理学，这将使他为离子通道的计算生物物理学职业做好准备。 此外，参与该奖项期间的职业发展活动将为候选人做好准备 奖励结束时独立。圣路易斯华盛顿大学麻醉学系 学术麻醉学领导者为离子频道研究提供了一个极好的支持环境 和身体科学家的发展。