Polyglutamine Folding and Aggregation - Molecular Structure and Pathways

聚谷氨酰胺折叠和聚集 - 分子结构和途径

基本信息

  • 批准号:
    1264021
  • 负责人:
  • 金额:
    $ 35.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-03-01 至 2016-02-29
  • 项目状态:
    已结题

项目摘要

Polyglutamine (or polyQ), a polymer consisting of glutamine repeat units, has been implicated in as many asnine neurodegenerative illnesses, including Huntington's disease (HD). An intriguing feature of the so-calledexpanded-polyQ-track diseases is that they only become manifest when the corresponding polyQ chainsexceed a certain critical length. Several hypotheses have been put forth to explain the onset of expandedpolyQdiseases. One hypothesis posits that, beyond a critical length, a polyQ molecule can adopt a foldedstructure that serves as a nucleus for the subsequent polymerization of additional molecules, thereby forming afibril. A more recent, alternative view proposes that several polyQ molecules can form a disordered aggregatethat, over time, gradually converts into a protofibril rich in ..-helical content. In this work, the PIs propose to use atomistic models of polyQ in aqueous solution to determine the structure of the nucleus and early aggregates, and to identify the molecular pathways throughwhich they form. More importantly, the PIs also propose to compare the results of simulations to 2-dimensionalinfrared (2D IR) spectroscopic measurements. To that end, the PIs will develop advanced simulation methods thatwill enable a thorough exploration of phase-space, as well as the pathways connecting different metastableconformational states, and they will develop tools that will permit prediction of 2D IR spectra directly from theresults of atomistic simulations. By engaging in a synergistic cycle of prediction and experimentation, they willarrive at a fundamental understanding of early-stage polyQ aggregation. Intellectual Merit: Theoretical and computational studies of the folding and aggregation of large PolyQmolecules in explicit water have been scarce. Studies of that nature, however, would provide much neededinsights into the genesis of a number of diseases. The research proposed will examine at an unprecedentedlevel of detail the ensembles of folded states adopted by polyQ, and will help determine how such states areinterconnected in the formation of small aggregates. The existence of such states and their dynamics will beassessed directly through 2D IR measurements, which will be interpreted in terms of the molecular modelsproposed in this work. The knowledge gained through this effort will not only provide insights into the onset ofHD, but will also yield important clues about the process of amyloid fibril formation by oligopeptides ingeneral. The computational challenges associated with our proposed research are staggering. A promisingarray of novel molecular modeling methods will be developed to meet those challenges. Such methods willadvance the state of the art in molecular simulation and will find applications in systems ranging frombiomolecules to complex fluids. The PIs anticipate that the combined 2D IR-computational approach to bedeveloped in this work will grow into a widely used technique for characterization of biomolecules.Broader Impacts: Huntington's disease currently afflicts 1 in 10,000 individuals. The toxic species are thesmall PolyQ aggregates of interest to this work; understanding the molecular origins of PolyQ folding andaggregation could provide new insights for development of therapeutic strategies. Beyond the beneficialimpact to society that would come with that understanding, the research proposed here offers a particularlyrelevant context in which to engage high-school children in science. The PIs propose to capitalize on thatopportunity by developing a workshop on protein aggregation and neurodegenerative disorders aimed at highschool students from under-represented minority backgrounds. By taking advantage of the computer expertiseof students involved in our proposed research, they will also propose to develop a strategy aimed at introducingmiddle-school and high-school students to computer programming early in their careers.
聚谷氨酰胺(polyQ)是一种由谷氨酰胺重复单元组成的聚合物,与多达9种神经退行性疾病有关,包括亨廷顿舞蹈病(HD)。所谓的扩展多q轨道疾病的一个有趣的特征是,只有当相应的多q链超过一定的临界长度时,它们才会显现出来。已经提出了几种假说来解释扩张性多病的发病。一种假设认为,超过临界长度后,polyQ分子可以采用折叠结构,作为随后聚合其他分子的核,从而形成原纤维。最近,另一种观点提出,几个多q分子可以形成一个无序的聚集体,随着时间的推移,逐渐转化为富含蛋白质的原纤维。螺旋的内容。在这项工作中,pi建议使用水溶液中聚q的原子模型来确定核和早期聚集体的结构,并确定它们形成的分子途径。更重要的是,pi还建议将模拟结果与二维红外光谱测量结果进行比较。为此,pi将开发先进的模拟方法,以实现对相空间的彻底探索,以及连接不同亚稳构象态的途径,他们将开发工具,允许直接从原子模拟结果预测二维红外光谱。通过参与预测和实验的协同循环,他们将对早期多q聚集有一个基本的了解。智力优势:关于大聚q分子在显性水中折叠和聚集的理论和计算研究很少。然而,这种性质的研究将为许多疾病的起源提供非常需要的见解。提出的研究将以前所未有的详细水平检查polyQ所采用的折叠态的集合,并将有助于确定这些状态如何在形成小聚集体时相互连接。这些状态的存在及其动力学将通过二维红外测量直接评估,这将根据本工作中提出的分子模型进行解释。通过这一努力获得的知识不仅将提供对hd发病的深入了解,而且还将提供关于淀粉样蛋白纤维形成过程的重要线索。与我们提出的研究相关的计算挑战是惊人的。一系列有希望的新型分子建模方法将被开发出来以应对这些挑战。这些方法将推动分子模拟技术的发展,并将在从生物分子到复杂流体的系统中得到应用。pi预计,在这项工作中开发的结合二维红外计算方法将发展成为一种广泛使用的生物分子表征技术。更广泛的影响:亨廷顿舞蹈症目前每10000人中就有1人患病。有毒物种是本工作感兴趣的小PolyQ聚集体;了解PolyQ折叠和聚集的分子起源可以为开发治疗策略提供新的见解。除了这种理解对社会的有益影响之外,这里提出的研究还提供了一个特别相关的背景,让高中生参与科学。pi建议利用这一机会,针对来自代表性不足的少数民族背景的高中生,开展一个关于蛋白质聚集和神经退行性疾病的研讨会。通过利用参与我们提议的研究的学生的计算机专业知识,他们还将提出一项旨在让初高中学生在职业生涯早期接触计算机编程的策略。

项目成果

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Juan De Pablo其他文献

Juan De Pablo的其他文献

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{{ truncateString('Juan De Pablo', 18)}}的其他基金

Collaborative Research: DMREF: Accelerated Design of Redox-Active Polymers for Metal-Free Batteries
合作研究:DMREF:无金属电池氧化还原活性聚合物的加速设计
  • 批准号:
    2119673
  • 财政年份:
    2021
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
Sustainable Materials and Manufacturing Virtual Square Table
可持续材料和制造虚拟方桌
  • 批准号:
    2127823
  • 财政年份:
    2021
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
NRT-HDR: AI-enabled Molecular Engineering of Materials and Systems (AIMEMS) for Sustainability
NRT-HDR:支持人工智能的材料和系统分子工程 (AIMEMS) 实现可持续发展
  • 批准号:
    2022023
  • 财政年份:
    2020
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
Planning Grant: Engineering Research Center for Microscale Autonomous Device Engineering (MADE)
规划资助:微型自主设备工程工程研究中心(MADE)
  • 批准号:
    1840557
  • 财政年份:
    2018
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
EFRI CEE: Epigenomic Regulation Over Multiple Length Scales: Understanding Chromatin Modifications Through Label Free Imaging and Multi-Scale Modeling
EFRI CEE:多个长度尺度的表观基因组调控:通过无标签成像和多尺度建模了解染色质修饰
  • 批准号:
    1830969
  • 财政年份:
    2018
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
MRI: Acquisition of a high-performance GPU-based computer for advanced multiscale materials modeling
MRI:购买基于 GPU 的高性能计算机,用于高级多尺度材料建模
  • 批准号:
    1828629
  • 财政年份:
    2018
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
Chromatin Structure and Dynamics from Nanometer to Micrometer Length Scales
从纳米到微米长度尺度的染色质结构和动力学
  • 批准号:
    1818328
  • 财政年份:
    2018
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
Frontiers of Molecular Design and Engineering - Junior Researcher Travel Scholarships
分子设计与工程前沿 - 初级研究员旅行奖学金
  • 批准号:
    1840839
  • 财政年份:
    2018
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
A Unified Framework for Description of Lyotropic and Active Liquid Crystals Far from Equilibrium
描述远离平衡态的溶致液晶和活性液晶的统一框架
  • 批准号:
    1710318
  • 财政年份:
    2017
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Standard Grant
Fundamental studies of liquid crystal nanodroplets
液晶纳米液滴的基础研究
  • 批准号:
    1410674
  • 财政年份:
    2014
  • 资助金额:
    $ 35.5万
  • 项目类别:
    Continuing Grant

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开发新的算法和概念来理解蛋白质折叠、错误折叠和聚集
  • 批准号:
    RGPIN-2019-03958
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