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Computational modeling of the mechanisms of microtubule disassembly by biological nanomachines

生物纳米机器微管分解机制的计算模型

基本信息

批准号：
1817948
负责人：
Ruxandra Dima
金额：
$ 78.79万
依托单位：
University of Cincinnati Main Campus
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1817948&HistoricalAwards=false
关键词：
Computational modeling mechanisms microtubule disassembly

项目摘要

Cells contain molecular machines consisting of protein complexes that convert chemical energy into mechanical work. These machines use the work to help either assemble or disassemble cellular structures during vital cell processes. Understanding the mechanisms of action of these biological machines and their relationship with conformational changes in their substrates are among the challenges of modern molecular biology. This project uses computational modeling at multiple scales to elucidate how a class of molecular machines associated with microtubules accomplishes the severing of this largest structure in the cytoskeleton, whose dynamic organization and rearrangement is an essential process of cell division, motility, and development. This research will address a critical gap in our understanding of the dynamic properties of microtubules and their complexes with microtubule associated proteins undergoing wear and their dependence on the magnitude and geometry of mechanical input and will lead to a better understanding of how molecular machines work. The project will provide education and training of undergraduate and graduate students in computational biophysical chemistry by involving them in interdisciplinary scientific projects and increase the participation of groups underrepresented in science through the outreach at local Cincinnati Public School and through research experience opportunities for freshmen students participating in the "Women in Science and Engineering" program at the University of Cincinnati. The results of the project will be disseminated to the public by the investigator, postdoc, and students through publications, conference presentations, and visits to local schools. This project will elucidate the major remodeling action of microtubules performed by severing enzymes from the ATPases Associated with various cellular Activities (AAA+) family. The multiscale simulations will determine molecular and thermodynamic parameters that characterize the breaking of a microtubule filament according to the proposed severing mechanisms. Because the action of AAA+ proteins is known to involve the application of pulling forces on their substrate proteins, in this project simulations that can reach the long time and length-scales required to follow the action of severing enzymes, primarily katanin in its hexameric functional states, will be complemented by experiments conducted by collaborators to extract markers of the unfoldase action on microtubules. Furthermore, the contribution of allosteric transitions between the active states of these hexameric enzymes to microtubule disassembly will be established. The combination of coarse-grained simulations and experiments will ultimately provide quantitative insight into the power stroke action of severing enzymes.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.

细胞包含由蛋白质复合物组成的分子机器，这些蛋白质复合物将化学能转化为机械功。这些机器使用工作来帮助组装或拆卸细胞结构在重要的细胞过程。了解这些生物机器的作用机制及其与底物构象变化的关系是现代分子生物学的挑战之一。该项目使用多尺度的计算建模来阐明一类与微管相关的分子机器如何完成细胞骨架中这个最大结构的切断，其动态组织和重排是细胞分裂，运动和发育的重要过程。这项研究将解决我们对微管及其与微管相关蛋白质的复合物的动态特性的理解中的一个关键空白，这些复合物经历磨损以及它们对机械输入的大小和几何形状的依赖，并将导致更好地理解分子机器如何工作。该项目将为本科生和研究生提供计算生物物理化学方面的教育和培训，让他们参与跨学科科学项目，并通过在当地辛辛那提公立学校开展外联活动以及为参加辛辛那提大学“科学和工程领域妇女”方案的新生提供研究经验机会，增加在科学领域代表性不足的群体的参与。该项目的结果将通过出版物、会议报告和访问当地学校的方式，由研究人员、博士后和学生向公众传播。本计画将阐明与各种细胞活性相关的三磷酸腺苷酶（AAA+）家族中的酶对微管的主要重塑作用。多尺度模拟将确定分子和热力学参数，其特征在于根据提出的切断机制的微管细丝的断裂。由于已知AAA+蛋白质的作用涉及对其底物蛋白施加拉力，因此在该项目中，模拟可以达到跟踪切断酶（主要是处于六聚体功能状态的卡他宁）作用所需的长时间和长度尺度，将通过合作者进行的实验来补充，以提取微管上展开酶作用的标记物。此外，这些六聚体酶的活性状态之间的变构转换微管拆卸的贡献将被建立。粗粒度的模拟和实验的结合将最终提供定量的洞察切断酶的动力冲程行动。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The quaternary question: Determining allostery in spastin through dynamics classification learning and bioinformatics

DOI：
10.1063/5.0139273
发表时间：
2023-03-28
期刊：
JOURNAL OF CHEMICAL PHYSICS
影响因子：
4.4
作者：
Kelly，Maria S.;Macke，Amanda C.;Dima，Ruxandra I.
通讯作者：
Dima，Ruxandra I.

Molecular investigations into the unfoldase action of severing enzymes on microtubules

切断酶对微管的解折叠酶作用的分子研究

DOI：
10.1002/cm.21606
发表时间：
2020
期刊：
Cytoskeleton
影响因子：
2.9
作者：
Varikoti, Rohith A.;Macke, Amanda C.;Speck, Virginia;Ross, Jennifer L.;Dima, Ruxandra I.
通讯作者：
Dima, Ruxandra I.

Microtubule Severing Enzymes Oligomerization and Allostery: A Tale of Two Domains

微管切断酶寡聚化和变构：两个域的故事

DOI：
10.1021/acs.jpcb.2c05288
发表时间：
2022
期刊：
The Journal of Physical Chemistry B
影响因子：
0
作者：
Macke, Amanda C.;Kelly, Maria S.;Varikoti, Rohith Anand;Mullen, Sarah;Groves, Daniel;Forbes, Clare;Dima, Ruxandra I.
通讯作者：
Dima, Ruxandra I.

Modeling the Mechanical Response of Microtubule Lattices to Pressure

模拟微管晶格对压力的机械响应