Collaborative Research: Tackling Functional Protein States at Atomic Detail by Integrating Weighted Ensemble Simulations with Magnetic Resonance Restraints

合作研究：通过将加权集成模拟与磁共振约束相结合来解决原子细节上的功能蛋白质状态

• 批准号: 2112871
• 负责人: Lillian Chong
• 金额: $ 85.6万
• 依托单位: University of Pittsburgh
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2112871&HistoricalAwards=false
• 关键词: Collaborative; Research; Tackling; Functional; Protein

This project is designed to characterize the alternate structures of proteins—the workhorses of life whose functions in biology are determined by their structures. A major challenge to characterizing these so-called “functional structures” is that these structures are often too diverse or fleeting to be captured by experimental techniques at the level of individual atoms. An unmet need is therefore a strategy that can determine the structures of functional protein structures at the atomic level and even more crucially, a strategy that can provide insights into how the functional structures interconvert. This project will develop a new software tool that can determine the functional structures of proteins, how the proteins move to convert from one structure to another, and the rates at which the structures interconvert. This tool combines the use of computer simulations with distances within proteins that are measured by experiments and will be made available through a popular, freely available WESTPA simulation software package. This interdisciplinary, collaborative project is providing a valuable training ground for graduate and undergraduate students participating in the research, and is supporting diverse educational and outreach activities, including biennial WESTPA software workshops to provide training to the scientific community in using the new tool for determining the functional structures of proteins. A new frontier in biophysics has been the structural characterization of protein functional states. Proteins are the workhorses of life and their functions are determined by their structures. A major challenge to characterizing protein structures is that many proteins adopt not just a single structural state, but alternate states that are relevant to the biological functions of the proteins. Due to the diversity and often transient nature of such functional states, the determination of their structures at the atomic level has been elusive to experimental techniques. An unmet need is therefore a strategy that can generate atomically detailed structures of functional states, and even more crucially, a strategy that can provide detailed insight into the pathways for interconversion between the states and corresponding kinetics. A key advance of the project is the development of a general strategy that integrates sparse distance restraints from magnetic resonance experiments with rigorous simulations to provide atomic level structures and dynamics of functional protein states. This project will provide a new simulation tool that will be made available to the scientific community through the freely available WESTPA software. To further enhance the accessibility of the software, the WESTPA software will be integrated with the Orion cloud-computing platform on Amazon Web Services, the world’s largest on-demand, cloud-computing facility. This project is funded by the Molecular Biophysics Cluster in the Division of Molecular and Cellular Biosciences, with partial co-funding from the Chemical Measurement and Imaging Program in the Division of Chemistry.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.

该项目旨在表征蛋白质的替代结构 - 生物学功能由其结构决定的生命的主力。表征这些所谓的“功能结构”的主要挑战是，这些结构通常太多或短暂而无法通过单个原子水平的实验技术捕获。因此，未满足的需求是可以在原子水平上确定功能蛋白结构的结构，甚至更全面的策略，该策略可以提供有关功能结构如何相互互换的见解。该项目将开发一种新的软件工具，该工具可以确定蛋白质的功能结构，蛋白质如何从一种结构转换为另一种结构以及结构互连的速率。该工具将计算机仿真的使用与蛋白质内的距离结合在一起，这些蛋白质通过实验测量，并将通过流行的，免费的Westpa仿真软件包提供。这个跨学科的合作项目为研究生和本科生的研究生提供了宝贵的培训理由，并支持潜水员的教育和外展活动，包括两年期Westpa软件讲习班，以使用新工具为科学界提供培训，以使用新工具来确定蛋白质的功能结构。生物物理学的新领域一直是蛋白质功能状态的结构表征。蛋白质是生命的工作主场，其功能取决于其结构。表征蛋白质结构的主要挑战是，许多蛋白质不仅采用单一的结构状态，而且采用与蛋白质生物学功能相关的替代状态。由于这种功能状态的多样性和经常性质，因此在原子水平上的结构的确定是实验技术难以捉摸的。因此，未满足的需求是一种可以生成功能状态的原子详细结构，甚至更全面的策略，该策略可以详细介绍对状态和相应动力学之间互连的途径的详细见解。该项目的关键进步是开发一般策略，该策略将磁共振实验的稀疏距离限制与严格的模拟相结合，以提供功能蛋白态的原子水平结构和动力学。该项目将提供一种新的仿真工具，该工具将通过免费的可用Westpa软件提供给科学界。为了进一步增强该软件的可访问性，Westpa软件将与Amazon Web Services上的Orion云计算平台集成在一起，Amazon Web Services是世界上最大的按需云计算设施。该项目由分子和细胞生物科学划分的分子生物物理学群集资助，并从化学测量和成像计划中获得了部分共同资助。该奖项反映了NSF的法定任务，并以评估基金会的智力优点和广泛的影响来评估NSF的法定任务。

项目成果

Direct observation of negative cooperativity in a detoxification enzyme at the atomic level by Electron Paramagnetic Resonance spectroscopy and simulation

• DOI: 10.1002/pro.4770
• 发表时间: 2023-10-01
• 期刊: PROTEIN SCIENCE
• 影响因子: 8
• 作者: Bogetti，Xiaowei;Bogetti，Anthony;Saxena，Sunil
• 通讯作者: Saxena，Sunil

Integrating Electron Paramagnetic Resonance Spectroscopy and Computational Modeling to Measure Protein Structure and Dynamics

• DOI: 10.1002/cplu.202300506
• 发表时间: 2023-10-25
• 期刊: CHEMPLUSCHEM
• 影响因子: 3.4
• 作者: Bogetti，Xiaowei;Saxena，Sunil
• 通讯作者: Saxena，Sunil

A Suite of Advanced Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v2.0]

WESTPA 2.0 罕见事件采样软件的一套高级教程 [文章 v2.0]

• DOI: 10.33011/livecoms.5.1.1655
• 发表时间: 2022
• 期刊: Living Journal of Computational Molecular Science
• 作者: Bogetti, Anthony T.;Leung, Jeremy M.;Russo, John D.;Zhang, She;Thompson, Jeff P.;Saglam, Ali S.;Ray, Dhiman;Abraham, Rhea C.;Faeder, James R.;Andricioaei, Ioan
• 通讯作者: Andricioaei, Ioan