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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：
2142727
负责人：
Arieh Warshel
金额：
$ 150万
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：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2142727&HistoricalAwards=false
关键词：
Computer Simulations proteins Molecular Machines

项目摘要

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.

在过去的几十年里，我们见证了人类健康分子基础研究的巨大进步。然而，详细的量化理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节，在G蛋白中，这些蛋白的复合体及其辅助因子调节细胞内的信号传递和运输过程。同样重要的是理解能量到达化合物三磷酸腺苷在特殊蛋白质中的使用，为生物机器提供燃料，并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生物马达的定向运动问题，生物马达在肌肉、心脏和神经细胞中产生方向力，这些细胞经常因功能故障而涉及疾病。同样，了解G蛋白偶联受体(GPCRs)的作用对于更清楚地了解不同激素等外部因素激活细胞过程的方式是至关重要的。该协会作为“科学大使”，与儿童和年轻人接触，以吸引他们对STEM领域的兴趣。该协会开发了研究溶液中、RasGAP、EF-Tu和ATPase中的磷酸水解反应的方法。利用这些方法，Pi的团队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。参比溶液反应的从头算QM/MM研究是在PI的实验室中进行的，并对G蛋白和ATPase的相应表面进行了评估。对生物马达、F0F1-ATP合酶和肌球蛋白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，重点是了解突变对马达效率的作用；(Ii)关于肌球蛋白的详细作用和单向性的研究；(Iii)GPCRs的研究，重点是μ阿片受体的激活途径；(4)G蛋白的系统研究，探索EF-Tu通过从头算QM/MM的作用，并努力建立激活过程的变构控制。该项目由分子和细胞生物科学部分子生物物理学分部资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Natural Evolution Provides Strong Hints about Laboratory Evolution of Designer Enzymes.

DOI：
10.1073/pnas.2207904119
发表时间：
2022-08-02
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
通讯作者：

Assessing the Catalytic Role of Native Glucagon Amyloid Fibrils

评估天然胰高血糖素淀粉样原纤维的催化作用

DOI：
10.1021/acscatal.4c00452
发表时间：
2024
期刊：
ACS Catalysis
影响因子：
12.9
作者：
Nandi, Ashim;Zhang, Aoxuan;Arad, Elad;Jelinek, Raz;Warshel, Arieh
通讯作者：
Warshel, Arieh

Electrostatic influence on IL-1 transport through the GSDMD pore.

DOI：
10.1073/pnas.2120287119
发表时间：
2022-02-08
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Xie WJ;Xia S;Warshel A;Wu H
通讯作者：
Wu H

Enhancing computational enzyme design by a maximum entropy strategy.

DOI：
10.1073/pnas.2122355119
发表时间：
2022-02-15
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Xie WJ;Asadi M;Warshel A
通讯作者：
Warshel A

Exploring the Role of Chemical Reactions in the Selectivity of Tyrosine Kinase Inhibitors.

探索化学反应在酪氨酸激酶抑制剂选择性中的作用。