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.

在过去的几十年中，我们在人类健康的分子基础研究中目睹了巨大的进步。但是，详细的定量理解仍然存在至关重要的需求。例如，需要理解G蛋白对生命过程的控制和介导，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传输过程。同样重要的是了解能量到达在专用蛋白质中的能源到达复合ATP来燃烧生物学机器并控制关键的能量转换过程。一个需要详细理解的相关问题是生物电动机的定向运动问题，这些动作在肌肉，心脏和神经细胞中产生了定向力，而这些力通常由于功能不良而导致疾病。同样，对G蛋白偶联受体（GPCR）的作用的理解对于对外部因素（例如不同的骑马）的方式更清晰地观察了激活细胞过程至关重要。 PI充当“科学大使”，并与儿童和年轻人互动以吸引他们对STEM地区的兴趣。 PI开发了研究溶液中磷酸盐水解反应的方法，在RASGAP，EF-TU和ATPases中。使用这些方法，PI的组探讨了导致癌症的突变的关键作用，并确定了基本的变构机制以及化学能转化为工作的机制。在PI的实验室中，对参考溶液反应的QM/MM研究进行了QM/MM研究。还对生物电动机F0F1-ATP合酶和肌球蛋白V进行了类似的研究。当前的项目将在以下方面并行移动：（i）对分子机器的作用的持续研究，研究旋转电机的作用，重点是理解突变对电动机效率的作用；（ii）研究肌球蛋白的详细作用和单向性；（iii）针对μ阿片受体的激活途径的GPCR的研究；（iv）对G蛋白的系统研究，探索从头算QM/mm的EF-TU的作用，并努力建立对激活过程的变构控制。该项目由分子和细胞生物科学部的分子生物物理学集群资助。该奖项反映了NSF的法定任务，并使用基金会的智力优点和更广泛的影响审查标准，通过评估诚实地认为通过评估。

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

In Defense of Merit in Science

捍卫科学价值

DOI：
10.35995/jci03010001
发表时间：
2023
期刊：
Journal of Controversial Ideas
影响因子：
0
作者：
Abbot, D.;Bikfalvi, A.;Bleske-Rechek, A.L.;Bodmer, W.;Boghossian, P.;Carvalho, C.M.;Ciccolini, J.;Coyne, J.A.;Gauss, J.;Gill, P.M.W.
通讯作者：
Gill, P.M.W.