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Structure Function Correlation of G-Proteins

G 蛋白的结构功能相关性

基本信息

批准号：
1243719
负责人：
Arieh Warshel
金额：
$ 87.33万
依托单位：
University of Southern California
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：
2013-04-01 至 2018-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1243719&HistoricalAwards=false
关键词：
Structure Function Correlation Proteins

项目摘要

The objective of this project is to obtain quantitative correlations between the structure and function of G-proteins. Obtaining a reliable detailed molecular description of the action of G-proteins can have a far reaching impact on the understanding key processes in the cell, by providing a more quantitative picture on the communication of information in the cell. Previous studies conducted in this project developed computer simulation methods to study GTP hydrolysis that is controlled by G-proteins. These simulations explored the key role of protein residues whose mutations lead to major change in activity and indicated that these residues act by modulating the coupling between the barrier for the chemical step and structural changes. This idea has been further validated by studies of the activation of the EF-Tu protein, which is involved in the elongation of the amino acid chain during protein synthesis. Attempts to confirm the above findings and to reach more unique conclusions involved systematic quantum mechanical ab initio studies of phosphate hydrolysis in solution, as well as a preliminary combined quantum (ab initio) / molecular mechanics (QM/MM) study of the activation of the protein Ras by the protein GAP. These studies reproduced key experimental findings while giving new insights into the nature of the free energy surface of the reaction. Further advances have been made in studying the conversion of chemical energy to work by the protein F1-ATPase and in studies of the unique unidirectional motions in this and in related systems. This project is placed now at a pivotal point, where it is poised to exploit the above progress and to move in parallel on the following fronts: (i) Further exploration of the activation of EF-Tu and the related protein EF-G , during the protein synthesis process. (ii) Continuing the studies of the chemical and conformational coupling in F1-ATPase. (iv) Exploring the action of G protein coupled receptors (GPCRs) which are responsible for the majority of cellular response to hormones and neurotransmitters. (iii) Conducting comparative studies of the action of different G-proteins and determining both the common and different catalytic factors (v) Exploring the information transfer in RasAGP and related systems by double mutations analysis (vi) Pushing for a consensus on the nature of the GTPase reactions by systematic ab initio QM/MM free energy calculations.The advances in the above research will be integrated into teaching and training programs. The PI will develop a computer-modeling course for students. Movies that illustrate the process of cellular signal transduction and its molecular foundations will be produced. The movies will be distributed to high schools, where they should encourage young people to pursue research in this field.

这个项目的目标是获得G蛋白结构和功能之间的定量相关性。通过提供关于细胞内信息交流的更定量的图像，获得对G蛋白作用的可靠的详细的分子描述可以对理解细胞中的关键过程产生深远的影响。该项目以前的研究开发了计算机模拟方法来研究由G-蛋白控制的GTP水解酶。这些模拟探索了蛋白质残基的关键作用，这些残基的突变导致活性的主要变化，并表明这些残基通过调节化学步骤的屏障和结构变化之间的耦合来发挥作用。对EF-Tu蛋白激活的研究进一步验证了这一观点，EF-Tu蛋白参与了蛋白质合成过程中氨基酸链的延长。为了证实上述发现并得出更独特的结论，涉及到对溶液中磷酸水解的系统量子力学从头算研究，以及对蛋白质GAP激活蛋白质RAS的初步结合量子力学(从头算)/分子力学(QM/MM)研究。这些研究复制了关键的实验结果，同时对反应的自由能表面的性质提供了新的见解。在研究蛋白质F1-ATPase将化学能转化为功以及在该系统和相关系统中独特的单向运动方面取得了进一步的进展。该项目现在正处于一个关键时刻，它准备利用上述进展，并在以下方面平行推进：(I)进一步探索蛋白质合成过程中EF-Tu和相关蛋白质EF-G的激活。(2)继续F1-ATPase的化学偶联和构象偶联的研究。(4)探索G蛋白偶联受体(GPCRs)的作用，GPCRs负责细胞对激素和神经递质的大部分反应。(Iii)对不同G蛋白的作用进行比较研究，确定共同和不同的催化因子。(V)通过双突变分析探索RasAGP及其相关系统中的信息传递(Vi)通过系统的从头计算QM/MM自由能计算，推动就GTP酶反应的性质达成共识。上述研究的进展将整合到教学和培训计划中。PI将为学生开发一门计算机建模课程。将制作说明细胞信号转导过程及其分子基础的电影。这些电影将被分发到高中，在那里他们应该鼓励年轻人在这个领域从事研究。