Computer Simulations of G-proteins and Molecular Machines

了解细胞中的活动过程如何支配和控制主要的生物功能，如信号传导和分子马达，是生物物理学的一个核心问题。例如，需要详细了解g蛋白对生命过程的控制和调解，其中g蛋白及其辅助因子的复合物调节细胞中的信号转导和运输过程。同样，了解ATP如何被用来为生物机器提供燃料和控制关键的细胞过程也很重要。还需要详细了解在肌肉、心脏和神经细胞中产生力的生物马达的定向运动的起源。理解这些过程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研究结果。该项目的成果将通过一般科学讲座和外展活动传播。此外，还将向科学界提供模拟软件包。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，已经由研究者和他的研究小组先前开发。这些进展现在将用于量化运动蛋白f1 - atp酶的化学和构象偶联，并探索肌球蛋白的力产生及其与肌肉运动的关系。此外，还将探讨gpcr的变构激活过程及其对GTP和GDP与g蛋白结合的影响，以及在控制核糖体功能中起主要作用的EF-Tu和EF-G的作用。从这个项目中产生的详细的定量理解可能会对推进基础生物学知识产生强烈的影响，并具有潜在的生物医学意义。

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.