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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

基本信息

批准号：
1707167
负责人：
Arieh Warshel
金额：
$ 100万
依托单位：
University of Southern California
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2022-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1707167&HistoricalAwards=false
关键词：
Computer Simulations proteins Molecular Machines

项目摘要

The understanding of how active processes in the cell govern and control major biological functions, such as signaling and molecular motors, is a central question in biophysics. For example, a detailed understanding is needed of the control and mediation of life processes by G-proteins, where complexes of these proteins with their cofactors regulate signal transduction and transport processes in the cell. Similarly, it is important to understand how ATP is used to fuel biological machines and control key cellular processes. A detailed understanding is also needed for the origin of the directional motions of biological motors that generate forces in muscular, cardiac and neural cells. Progress in understanding these processes require a close interaction between theory and experiment. This project aims to elucidate how biological molecules control cellular function at the molecular level using state of the art computational approaches using experimental data to validate the findings. Outcomes of this project will be disseminated via general scientific lectures and outreach activities. In addition, simulation packages will be made available to the scientific community. Powerful multiscale models, including quantum mechanics/molecular mechanics (QM/MM) approaches for exploring chemical processes in G-proteins and coarse grained models for studies of energy transduction have been previously developed by the investigator and his research group. Such developments will now be used to quantify the chemical and conformational coupling in the motor protein F1-ATPase and to explore the force generation in myosin and its relationship to muscles action. In addition, the allosteric activation process of GPCRs and its effect on the binding of GDP and GTP to G-proteins, as well as the action of EF-Tu and EF-G, which play major role in controlling the ribosome function, will be explored. The detailed quantitative understanding resulting from this project is likely to have a strong impact on advancing fundamental biological knowledge, as well as having potential biomedical implications.

理解细胞中活跃的过程如何控制和控制主要的生物功能，如信号和分子马达，是生物物理学中的一个中心问题。例如，需要详细了解G-蛋白对生命过程的控制和调节，其中这些蛋白与其辅助因子的复合体调节细胞中的信号转导和运输过程。同样，重要的是要了解ATP是如何用来为生物机器提供燃料和控制关键的细胞过程的。还需要详细了解生物马达的定向运动的起源，这些马达在肌肉、心脏和神经细胞中产生力。在理解这些过程方面的进展需要理论和实验之间的密切互动。该项目旨在阐明生物分子如何在分子水平上控制细胞功能，使用最先进的计算方法，使用实验数据来验证发现。该项目的成果将通过一般科学讲座和外联活动传播。此外，还将向科学界提供模拟包。这位研究者和他的研究小组已经开发了功能强大的多尺度模型，包括用于探索G蛋白化学过程的量子力学/分子力学(QM/MM)方法和用于研究能量转导的粗粒度模型。这些进展现在将被用于量化马达蛋白F1-ATPase中的化学和构象偶联，并探索肌球蛋白中的力产生及其与肌肉动作的关系。此外，还将探讨GPCRs的变构激活过程及其对GDP和GTP与G蛋白结合的影响，以及在核糖体功能调控中起主要作用的EF-Tu和EF-G的作用。这个项目产生的详细的量化理解可能会对推进基础生物学知识产生强烈影响，并具有潜在的生物医学意义。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative exploration of the molecular origin of the activation of GTPase

DOI：
10.1073/pnas.1319854110
发表时间：
2013-11
期刊：
Proceedings of the National Academy of Sciences
影响因子：
0
作者：
Ram Prasad B;N. V. Plotnikov;J. Lameira;A. Warshel
通讯作者：
Ram Prasad B;N. V. Plotnikov;J. Lameira;A. Warshel

Exploring, Refining, and Validating the Paradynamics QM/MM Sampling

DOI：
10.1021/jp304678d
发表时间：
2012-08-30
期刊：
JOURNAL OF PHYSICAL CHEMISTRY B
影响因子：
3.3
作者：
Plotnikov, Nikolay V.;Warshel, Arieh
通讯作者：
Warshel, Arieh

Simulating the dynamics of the mechanochemical cycle of myosin-V

DOI：
10.1073/pnas.1700318114
发表时间：
2017-02-28
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Mukherjee, Shayantani;Alhadeff, Raphael;Warshel, Arieh
通讯作者：
Warshel, Arieh

Exploring alternative catalytic mechanisms of the Cas9 HNH domain

DOI：
10.1002/prot.25796
发表时间：
2020-02
期刊：
Proteins: Structure
影响因子：
0
作者：
Li na Zhao;D. Mondal;A. Warshel
通讯作者：
Li na Zhao;D. Mondal;A. Warshel

Electrostatic origin of the mechanochemical rotary mechanism and the catalytic dwell of F1-ATPase

DOI：
10.1073/pnas.1117024108
发表时间：
2011-12-20
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Mukherjee, Shayantani;Warshel, Arieh
通讯作者：
Warshel, Arieh