NSF-BSF: Synergistic Multiscale Modeling and Single-Molecule Fluorescence Studies of the Dynamics and Function of AAA+ Protein Disaggregation Machines

NSF-BSF:AAA 蛋白质解聚机动力学和功能的协同多尺度建模和单分子荧光研究

基本信息

  • 批准号:
    2136816
  • 负责人:
  • 金额:
    $ 85.15万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-12-01 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

Disassembly of toxic protein aggregates is an essential quality control mechanism that ensures cell viability under stress conditions. This action is performed by ring-shaped AAA+ (ATPases Associated with diverse cellular Activities) biological nanomachines, such as Clp/Hsp100 (ClpB in bacteria or Hsp104 in yeast), which apply mechanical forces to extract protein molecules from aggregates and translocate them through narrow pores to assist their renaturation process. Understanding, at the microscopic level, the coupling between the conformational dynamics of the nanomachine and the mechanisms of substrate protein (SP) threading and disassembly will enable the elucidation of fundamental aspects of critical cellular processes. This project will synergistically combine hybrid multiscale computer simulations, performed in the lab of Prof. Stan at the University of Cincinnati, US, and single-molecule fluorescence resonance energy transfer (smFRET) experiments, performed in the lab of Prof. Haran at the Weizmann Institute, Israel. Increasing the participation of underrepresented minorities in computational sciences is at the center of educational and mentoring activities integrated with the biophysical research in this project. These activities will include outreach at Central State University (CSU), a Historically Black College and University, and research experience opportunities for underrepresented minorities at the University of Cincinnati. Further, science training programs will be offered for summer camp students at the Cincinnati Museum Center. The US-Israel exchange program included in this project will provide interdisciplinary experience and international perspective for students and postdocs. This project will address two key aspects in the mechanism of protein machines, namely the propagation of conformational transitions between subunits and the way substrates are being manipulated. A combination of unique single-molecule experiments and innovative simulations will be performed on ClpB and will reveal the real-time propagation of function-related conformational changes between the subunits of ClpB. Functional states and domain motions during the allosteric cycle of the machine will be measured using smFRET methodology over a broad range of timescales, from microseconds to seconds. Computer simulations, using smFRET-derived distances, will determine ClpB conformations associated with functional states and characterize motions between them. Coarse-grained simulations and analysis based on machine learning will be employed to this end. This project will also reveal how SPs are translocated through the ClpB lumen. SPs will be traced in real time on the single-molecule level as they interact with ClpB molecules. Novel hybrid multiscale computational models will complement the experiments and provide atomistic-level information on the mechanism of extraction of SPs from amorphous aggregates and their threading process. These studies will provide a new framework for the synergistic application of experiments and computations to nanomachines, with implications to multiple future studies.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
毒性蛋白质聚集体的降解是确保细胞在应激条件下存活的重要质量控制机制。这一作用是由环形AAA+(与多种细胞活动相关的ATP酶)生物纳米机器执行的,例如Clp/Hsp100(细菌中的ClpB或酵母中的Hsp104),它施加机械力从聚集体中提取蛋白质分子,并将它们通过狭窄的孔移位,以帮助它们的复性过程。理解,在微观层面上,纳米机器的构象动力学和底物蛋白(SP)线程和拆卸机制之间的耦合将使关键的细胞过程的基本方面的阐明。该项目将协同联合收割机混合多尺度计算机模拟,在美国辛辛那提大学Stan教授的实验室进行,和单分子荧光共振能量转移(smFRET)实验,在以色列魏茨曼研究所Haran教授的实验室进行。增加在计算科学中代表性不足的少数群体的参与是与该项目中的生物物理研究相结合的教育和指导活动的中心。这些活动将包括在中央州立大学(一所历史上的黑人学院和大学)开展外联活动,并为代表性不足的少数群体提供在辛辛那提大学进行研究的机会。此外,科学培训计划将提供夏令营的学生在辛辛那提博物馆中心。该项目中的美国-以色列交流项目将为学生和博士后提供跨学科的经验和国际视野。该项目将解决蛋白质机器机制中的两个关键方面,即亚基之间构象转换的传播和底物被操纵的方式。独特的单分子实验和创新模拟的组合将在ClpB上进行,并将揭示ClpB亚基之间功能相关构象变化的实时传播。在机器的变构周期期间的功能状态和域运动将使用smFRET方法在从微秒到秒的宽范围的时间尺度上测量。计算机模拟,使用smFRET衍生的距离,将确定ClpB构象与功能状态和它们之间的运动特征。为此,将采用基于机器学习的粗粒度模拟和分析。该项目还将揭示SP如何通过ClpB腔易位。 当SP与ClpB分子相互作用时,将在单分子水平上真实的实时追踪SP。新的混合多尺度计算模型将补充实验,并提供原子级的信息从无定形聚集体和线程过程中提取的SP的机制。这些研究将为纳米机器的实验和计算的协同应用提供一个新的框架,与多个未来的研究的影响。这个合作美国/以色列项目由美国国家科学基金会和以色列两国科学基金会支持。该奖项反映了NSF的法定使命,并通过使用基金会的知识价值和更广泛的影响审查进行评估,被认为值得支持的搜索.

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Allosteric communication in the gating mechanism for controlled protein degradation by the bacterial ClpP peptidase
  • DOI:
    10.1063/5.0139184
  • 发表时间:
    2023-03-28
  • 期刊:
  • 影响因子:
    4.4
  • 作者:
    Dayananda,Ashan;Dennison,T. S. Hayden;Stan,George
  • 通讯作者:
    Stan,George
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

George Stan其他文献

Probing allosteric communication in the ClpB AAA+ disaggregase
  • DOI:
    10.1016/j.bpj.2023.11.460
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Zhaocheng Zhang;Ashan Dayananda;Gilad Haran;George Stan
  • 通讯作者:
    George Stan
Probing allosteric mechanisms of the Hsp104 disaggregase using machine learning techniques
  • DOI:
    10.1016/j.bpj.2023.11.454
  • 发表时间:
    2024-02-08
  • 期刊:
  • 影响因子:
  • 作者:
    Tharushi Rajaguru;Sumedhi Jayasekara;Ashan Dayananda;George Stan
  • 通讯作者:
    George Stan
Conformational dynamics of the ClpB AAA+ protein disaggregase: molecular dynamics studies
  • DOI:
    10.1016/j.bpj.2021.11.500
  • 发表时间:
    2022-02-11
  • 期刊:
  • 影响因子:
  • 作者:
    Ashan Dayananda;Ruxandra I. Dima;George Stan
  • 通讯作者:
    George Stan

George Stan的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('George Stan', 18)}}的其他基金

Conference: "From Computational Biophysics to Systems Biology 2017" (CBSB2017) to be held on May 18-20, 2017 at the University of Cincinnati in Cincinnati, OH
会议:“从计算生物物理学到系统生物学 2017”(CBSB2017)将于 2017 年 5 月 18 日至 20 日在俄亥俄州辛辛那提市辛辛那提大学举行
  • 批准号:
    1740908
  • 财政年份:
    2017
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
Computational Modeling of Protein Degradation by Biological Nanomachines
生物纳米机器蛋白质降解的计算模型
  • 批准号:
    1516918
  • 财政年份:
    2015
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
CAREER: Computational Modeling of Biological Nanomachines - Protein Unfolding and Translocation by Clp ATPases
职业:生物纳米机器的计算模型 - Clp ATP 酶的蛋白质解折叠和易位
  • 批准号:
    0952082
  • 财政年份:
    2010
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Continuing Grant

相似国自然基金

枯草芽孢杆菌BSF01降解高效氯氰菊酯的种内群体感应机制研究
  • 批准号:
    31871988
  • 批准年份:
    2018
  • 资助金额:
    59.0 万元
  • 项目类别:
    面上项目
基于掺硼直拉单晶硅片的Al-BSF和PERC太阳电池光衰及其抑制的基础研究
  • 批准号:
    61774171
  • 批准年份:
    2017
  • 资助金额:
    63.0 万元
  • 项目类别:
    面上项目
B细胞刺激因子-2(BSF-2)与自身免疫病的关系
  • 批准号:
    38870708
  • 批准年份:
    1988
  • 资助金额:
    3.0 万元
  • 项目类别:
    面上项目

相似海外基金

Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization
合作研究:NSF-BSF:细胞粘附分子如何控制神经元电路布线:结合亲和力、结合可用性和亚细胞定位
  • 批准号:
    2321481
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Continuing Grant
Collaborative Research: NSF-BSF: How cell adhesion molecules control neuronal circuit wiring: Binding affinities, binding availability and sub-cellular localization
合作研究:NSF-BSF:细胞粘附分子如何控制神经元电路布线:结合亲和力、结合可用性和亚细胞定位
  • 批准号:
    2321480
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Continuing Grant
NSF-BSF: Many-Body Physics of Quantum Computation
NSF-BSF:量子计算的多体物理学
  • 批准号:
    2338819
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Continuing Grant
Collaborative Research: NSF-BSF: Under Pressure: The evolution of guard cell turgor and the rise of the angiosperms
合作研究:NSF-BSF:压力之下:保卫细胞膨压的进化和被子植物的兴起
  • 批准号:
    2333889
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
Collaborative Research: NSF-BSF: Under Pressure: The evolution of guard cell turgor and the rise of the angiosperms
合作研究:NSF-BSF:压力之下:保卫细胞膨压的进化和被子植物的兴起
  • 批准号:
    2333888
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Continuing Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
  • 批准号:
    2400195
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
NSF-BSF: Collaborative Research: Solids and reactive transport processes in sewer systems of the future: modeling and experimental investigation
NSF-BSF:合作研究:未来下水道系统中的固体和反应性输送过程:建模和实验研究
  • 批准号:
    2134594
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
NSF-BSF Combinatorial Set Theory and PCF
NSF-BSF 组合集合论和 PCF
  • 批准号:
    2400200
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
NSF-BSF: CDS&E: Tensor Train methods for Quantum Impurity Solvers
NSF-BSF:CDS
  • 批准号:
    2401159
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Continuing Grant
NSF-BSF: Collaborative Research: AF: Small: Algorithmic Performance through History Independence
NSF-BSF:协作研究:AF:小型:通过历史独立性实现算法性能
  • 批准号:
    2420942
  • 财政年份:
    2024
  • 资助金额:
    $ 85.15万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了