Computer Simulations of G-proteins and Molecular Machines

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，详细的定量了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调解，其中这些蛋白质的复合物及其辅助因子调节细胞中的信号传递和运输过程。同样重要的是理解在特殊蛋白质中使用能量到达化合物ATP来为生物机器提供燃料和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，在肌肉、心脏和神经细胞中产生定向力的生物马达的定向运动问题，这些运动通常与功能缺陷引起的疾病有关。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”，与儿童和青少年接触，吸引他们对STEM领域的兴趣。PI开发了研究溶液、RasGAP、EF-Tu和ATPases中磷酸水解反应的方法。利用这些方法，PI的小组探索了突变导致癌症的关键作用，并确定了潜在的变构机制，以及化学能转化为功的机制。参考溶液反应的从头算QM/MM研究和相应表面g蛋白和atp酶的评价在PI实验室进行。对生物马达、F0F1-ATP合成酶和肌球蛋白v也进行了类似的研究。目前的项目将在以下方面并行进行：(i)继续研究分子机器的作用，检查旋转马达的作用，重点了解突变对马达效率的作用；（ii）肌凝蛋白的详细作用和单向性研究；（iii）以μ-阿片受体激活途径为重点的gpcr研究；（iv） g蛋白的系统研究，通过从头算QM/MM探索EF-Tu的作用，并努力建立活化过程的变构控制。该项目由分子和细胞生物科学部的分子生物物理集群资助。该奖项反映了美国国家科学基金会的法定使命，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。

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.