Computer Simulations of G-proteins and Molecular Machines

G 蛋白和分子机器的计算机模拟

基本信息

  • 批准号:
    2142727
  • 负责人:
  • 金额:
    $ 150万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Standard Grant
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

Over the past several decades we have witnessed tremendous advances in the studies of the molecular basis of human health. However, detailed quantitative understanding is still in a crucial need. For example, understanding is needed of the control and mediation of life processes by G-proteins where the complexes of these proteins, with their cofactors, regulate signal transfer and transport processes in the cell. Equally important is the understanding of the use of the energy reach compound ATP in specialized proteins to fuel biological machines and to control key energy conversion processes. A related issue that requires detailed understanding, is the problem of directional motions of biological motors that generate directional force in muscular, cardiac, and neural cells that are often involved in diseases due to faulty functions. Similarly, the understanding of the action of G protein coupled receptors (GPCRs) is crucial for having a clearer view of the way external factors such as different hormones activate cellular process. The PI serves as “Science Ambassador” and engages with children and young adults to attract their interest in STEM areas.The PI has developed methods for studying phosphate hydrolysis reactions in solution, in RasGAP, in EF-Tu and in ATPases. Using these methods, the PI’s group explored the key role of mutations leading to cancer and identified the underlying allosteric mechanism as well as, the mechanism by which chemical energy is converted to work. ab initio QM/MM studies of the reference solution reaction and evaluation of the corresponding surface in G-proteins and ATPases were conducted in the PI’s laboratory. Similar studies were also done with the biological motors, F0F1-ATP synthase, and myosin V. The current projects will move in parallel on the following fronts: (i) continue studies of the action of molecular machines, examining the action of rotary motors, with focus on understanding the role of mutations on the efficiency of the motors; (ii) studies on the detailed action and unidirectionality of myosins; (iii) studies of GPCRs focusing on the activation pathways of the μ-opioid receptor; and (iv) systematic studies of G-proteins, exploring the action of EF-Tu by ab initio QM/MM and work to establish the allosteric control of the activation process. This project was funded by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division.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.
在过去的几十年里,我们目睹了人类健康分子基础研究的巨大进步。然而,详细的定量理解仍然是至关重要的。例如,需要了解G蛋白对生命过程的控制和介导,其中这些蛋白质与其辅因子的复合物调节细胞中的信号传递和运输过程。同样重要的是了解如何使用能量到达化合物ATP在专门的蛋白质中为生物机器提供燃料并控制关键的能量转换过程。一个需要详细了解的相关问题是生物马达的定向运动问题,这些生物马达在肌肉、心脏和神经细胞中产生定向力,这些细胞通常因功能缺陷而参与疾病。同样,了解G蛋白偶联受体(GPCR)的作用对于更清楚地了解外部因素(如不同激素)激活细胞过程的方式至关重要。PI担任“科学大使”,与儿童和年轻人接触,吸引他们对STEM领域的兴趣。PI开发了研究溶液中磷酸盐水解反应的方法,在RasGAP,EF-Tu和ATP酶中。利用这些方法,PI的研究小组探索了导致癌症的突变的关键作用,并确定了潜在的变构机制以及化学能转化为工作的机制。 在PI实验室进行了参比溶液反应的从头算QM/MM研究以及G蛋白和ATP酶中相应表面的评价。目前的项目将在以下方面平行进行:(i)继续研究分子机器的作用,检查旋转电机的作用,重点是了解突变对电机效率的作用;(ii)研究肌球蛋白的详细作用和单向性;(iii)研究肌球蛋白的作用。(iii)GPCR的研究,重点是μ-阿片受体的激活途径;(iv)G蛋白的系统研究,通过从头算QM/MM探索EF-Tu的作用,并致力于建立激活过程的变构控制。该项目由分子和细胞生物科学部的分子生物物理学小组资助。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标准进行评估,被认为值得支持。

项目成果

期刊论文数量(14)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Assessing the Catalytic Role of Native Glucagon Amyloid Fibrils
评估天然胰高血糖素淀粉样原纤维的催化作用
  • DOI:
    10.1021/acscatal.4c00452
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    12.9
  • 作者:
    Nandi, Ashim;Zhang, Aoxuan;Arad, Elad;Jelinek, Raz;Warshel, Arieh
  • 通讯作者:
    Warshel, Arieh
Electrostatic influence on IL-1 transport through the GSDMD pore.
Enhancing computational enzyme design by a maximum entropy strategy.
Exploring the Role of Chemical Reactions in the Selectivity of Tyrosine Kinase Inhibitors.
探索化学反应在酪氨酸激酶抑制剂选择性中的作用。
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Arieh Warshel其他文献

Electrostatic influence of IL-1 transport through the GSDMD pore
  • DOI:
    10.1016/j.bpj.2021.11.897
  • 发表时间:
    2022-02-11
  • 期刊:
  • 影响因子:
  • 作者:
    Wenjun Xie;Shiyu Xia;Arieh Warshel;Hao Wu
  • 通讯作者:
    Hao Wu
Computational Enzyme Design: Refining Artificial Enzymes and Exploring Paths of Directed Evolution
  • DOI:
    10.1016/j.bpj.2010.12.1407
  • 发表时间:
    2011-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Maria P. Frushicheva;Arieh Warshel
  • 通讯作者:
    Arieh Warshel
External Electric Field in the Atomistic Simulation of Membrane Systems
  • DOI:
    10.1016/j.bpj.2010.12.2023
  • 发表时间:
    2011-02-02
  • 期刊:
  • 影响因子:
  • 作者:
    Anatoly Dryga;Arieh Warshel
  • 通讯作者:
    Arieh Warshel
Calculations of electrostatic energies in proteins. The energetics of ionized groups in bovine pancreatic trypsin inhibitor.
蛋白质静电能的计算。
  • DOI:
    10.1016/0022-2836(85)90411-5
  • 发表时间:
    1985
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    S. T. Russell;Arieh Warshel
  • 通讯作者:
    Arieh Warshel
Electrostatic Contribution to the Transition States Binding Free Energy Using Simplified Coarse Grained Model
  • DOI:
    10.1016/j.bpj.2009.12.252
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Maria P. Frushicheva;Arieh Warshel
  • 通讯作者:
    Arieh Warshel

Arieh Warshel的其他文献

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{{ truncateString('Arieh Warshel', 18)}}的其他基金

Computer Simulations of G-proteins and Molecular Machines
G 蛋白和分子机器的计算机模拟
  • 批准号:
    1707167
  • 财政年份:
    2017
  • 资助金额:
    $ 150万
  • 项目类别:
    Standard Grant
Structure Function Correlation of G-Proteins
G 蛋白的结构功能相关性
  • 批准号:
    1243719
  • 财政年份:
    2013
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant
Structure Function Correlation of G-Proteins
G 蛋白的结构功能相关性
  • 批准号:
    0836400
  • 财政年份:
    2009
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant
Structure Function Correlation of G-Proteins
G 蛋白的结构功能相关性
  • 批准号:
    0342276
  • 财政年份:
    2004
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant
Structure Function Correlation of G-Proteins
G 蛋白的结构功能相关性
  • 批准号:
    0003872
  • 财政年份:
    2001
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant
Structure Function Correlation of G-Proteins
G 蛋白的结构功能相关性
  • 批准号:
    9808638
  • 财政年份:
    1998
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant
Hydrophobic and Hydrophilic Forces in Membrane and Globular Proteins (Part II)
膜和球状蛋白质中的疏水力和亲水力(第二部分)
  • 批准号:
    8519194
  • 财政年份:
    1985
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant
Theoretical Studies of the Primary Event in the Visual Process
视觉过程中主要事件的理论研究
  • 批准号:
    8303385
  • 财政年份:
    1983
  • 资助金额:
    $ 150万
  • 项目类别:
    Continuing Grant

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Computer Simulations of G-proteins and Molecular Machines
G 蛋白和分子机器的计算机模拟
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通过 AFM 和计算机模拟进行蛋白质和新生多肽链的矢量折叠
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  • 财政年份:
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通过计算机模拟了解呼吸酶一氧化氮还原酶的功能
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    22770163
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电子转移蛋白质的计算机模拟
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蛋白质聚集的计算机模拟
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通过计算机模拟研究阿尔茨海默淀粉样蛋白组装途径
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  • 财政年份:
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