Structure Function Correlation of G-Proteins

本项目的目标是获得G蛋白的结构和功能之间的定量相关性。 获得G蛋白作用的可靠的详细分子描述可以对理解细胞中的关键过程产生深远的影响，通过提供细胞中信息交流的更定量的图片。本项目先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。这些模拟探索了蛋白质残基的关键作用，其突变导致活性的重大变化，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起作用。 这一想法已经通过EF-Tu蛋白的活化研究得到进一步验证，EF-Tu蛋白参与蛋白质合成期间氨基酸链的延伸。试图证实上述发现，并达到更独特的结论涉及系统的量子力学从头研究磷酸盐在溶液中的水解，以及初步的结合量子（从头）/分子力学（QM/MM）的蛋白质Ras的激活蛋白质GAP的研究。这些研究再现了关键的实验结果，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-ATP酶将化学能转化为功以及研究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点，它准备利用上述进展，并在以下方面平行移动：（i）在蛋白质合成过程中进一步探索EF-Tu和相关蛋白EF-G的激活。(ii)继续研究F1-ATP酶的化学和构象偶联。(iv)探索G蛋白偶联受体（GPCR）的作用，GPCR负责大多数细胞对激素和神经递质的反应。(iii)对不同G蛋白的作用进行比较研究，确定共同的和不同的催化因子（v）通过双突变分析探索RasAGP和相关系统中的信息传递（vi）通过系统的从头算QM/MM自由能计算推动对GTdR反应性质的共识。 PI将为学生开发计算机建模课程。 将制作说明细胞信号转导过程及其分子基础的电影。这些电影将分发给高中，鼓励年轻人在这一领域进行研究。

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.