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Collaborative Research: CIBR: Computational resources for modeling and analysis of realistic cell membranes

合作研究：CIBR：用于真实细胞膜建模和分析的计算资源

基本信息

批准号：
2011234
负责人：
Wonpil Im
金额：
$ 43.45万
依托单位：
Lehigh University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2011234&HistoricalAwards=false
关键词：
Collaborative Research CIBR Computational resources

项目摘要

Biological membranes are semi-permeable barriers that separate living cells from the environment and create intracellular compartments. They are composed of many types of lipids and are crowded with numerous transmembrane and peripheral membrane proteins. These proteins participate in all vital cellular processes, including biogenesis, energy and signal transduction, molecular transport, vesicular trafficking, cell motility, recognition, adhesion, and shape regulation. Despite the growing number of atomic structures of membrane proteins, the lack of information about their spatial positions and protein-lipid interactions in their native membranes impedes our understanding of molecular mechanisms of their folding, stability, function, and regulation. Motivated by rising demands in realistic representation of proteins in non-planar and deformable membranes with natural lipid compositions, we propose a creation of a high-capacity cyberinfrastructure for fast and reproducible assembly of membrane proteins with natural lipids to build flexible multicomponent biomembranes for subsequent structural analysis and molecular dynamics (MD) simulations. This project will promote synergy between scientific research and education by training computer science students in developing bioinformatics resources, by using the developed toolbox for teaching, and by providing training materials and web-based workshops for students and the user community to promote research experience in membrane simulations.This collaborative project will enhance and combine capabilities of the highly recognized and widely used PPM/OPM and CHARMM-GUI resources that have been developed by the research teams from the University of Michigan and Lehigh University. The project has three main components. First, the PPM (Positioning of Proteins in Membranes) method will be advanced for calculating the spatial arrangement and binding energy of proteins in deformable membranes characterized by diverse polarity profiles, asymmetry, charge, and curvature. Second, a new PPM/CHARMM-GUI toolbox will be developed by integrating the improved PPM method and CHARMM-GUI Membrane Builder to assemble native-like protein-lipid systems and provide input files for realistic simulations of biomembranes by various MD simulation packages. The open web-based platform will allow users of diverse expertise to easily setup and perform simulations of membrane proteins with known three-dimensional (3D) structures in deformable membranes with complex lipid composition. Third, native-like all-atom membrane systems for thousands of known membrane protein structures with natural lipids from eukaryotic and prokaryotic cells and organelles will be produced using this toolbox. The generated protein-lipid systems together with the inputs for MD simulations will be deposited in the improved and expanded OPM database (at opm.phar.umich.edu). These inputs can be directly used for state-of-the-art MD simulations of realistic cell membranes to assist in planning and interpreting experimental studies. The proposed toolbox (at charmm-gui.org) will significantly enhance the capacity of existing web resources for biomolecular simulations, while ensuring the long-awaited transition from modeling only transmembrane proteins to simulations of both transmembrane and peripheral proteins and their complexes in membranes; from artificial lipidThis 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.

生物膜是将活细胞与环境分开并形成细胞内隔室的半渗透屏障。它们由多种类型的脂质组成，并挤满了大量的跨膜蛋白和外周膜蛋白。这些蛋白质参与所有重要的细胞过程，包括生物发生、能量和信号转导、分子运输、囊泡运输、细胞运动、识别、粘附和形状调节。尽管膜蛋白的原子结构越来越多，但缺乏有关其空间位置和天然膜中蛋白质-脂质相互作用的信息，阻碍了我们对其折叠、稳定性、功能和调节的分子机制的理解。由于对具有天然脂质成分的非平面和可变形膜中蛋白质的真实表达的需求不断增长，我们建议创建一个高容量的网络基础设施，用于快速且可重复地组装膜蛋白与天然脂质，以构建灵活的多组分生物膜，用于后续的结构分析和分子动力学（MD）模拟。该项目将通过培训计算机科学专业的学生开发生物信息学资源、使用开发的教学工具箱以及为学生和用户社区提供培训材料和基于网络的研讨会来促进科学研究和教育之间的协同作用，以促进膜模拟的研究经验。该合作项目将增强和结合由英国大学研究团队开发的高度认可和广泛使用的 PPM/OPM 和 CHARMM-GUI 资源的功能。密歇根大学和里海大学。该项目由三个主要部分组成。首先，将改进PPM（膜中蛋白质的定位）方法，用于计算以不同极性分布、不对称性、电荷和曲率为特征的可变形膜中蛋白质的空间排列和结合能。其次，将通过集成改进的 PPM 方法和 CHARMM-GUI Membrane Builder 来开发新的 PPM/CHARMM-GUI 工具箱，以组装类似天然的蛋白质-脂质系统，并为各种 MD 模拟软件包对生物膜进行真实模拟提供输入文件。这个基于网络的开放平台将允许具有不同专业知识的用户轻松设置和执行具有复杂脂质成分的可变形膜中已知三维（3D）结构的膜蛋白的模拟。第三，使用该工具箱将使用来自真核和原核细胞和细胞器的天然脂质生产数千种已知膜蛋白结构的类似天然的全原子膜系统。生成的蛋白质-脂质系统以及 MD 模拟的输入将存储在改进和扩展的 OPM 数据库中（位于 opm.phar.umich.edu）。这些输入可直接用于真实细胞膜的最先进的 MD 模拟，以协助规划和解释实验研究。拟议的工具箱（位于 charmm-gui.org）将显着增强现有生物分子模拟网络资源的能力，同时确保期待已久的从仅模拟跨膜蛋白到模拟跨膜蛋白和外围蛋白及其膜复合物的转变；该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值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（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure, Dynamics, Receptor Binding, and Antibody Binding of the Fully Glycosylated Full-Length SARS-CoV-2 Spike Protein in a Viral Membrane.

DOI：
10.1021/acs.jctc.0c01144
发表时间：
2021-04-13
期刊：
Journal of chemical theory and computation
影响因子：
5.5
作者：
Choi YK;Cao Y;Frank M;Woo H;Park SJ;Yeom MS;Croll TI;Seok C;Im W
通讯作者：
Im W

Comparative Molecular Dynamics Simulation Studies of Realistic Eukaryotic, Prokaryotic, and Archaeal Membranes

真实真核生物、原核生物和古细菌膜的比较分子动力学模拟研究

DOI：
10.1021/acs.jcim.1c01514
发表时间：
2022
期刊：
Journal of Chemical Information and Modeling
影响因子：
5.6
作者：
Pogozheva, Irina D.;Armstrong, Grant A.;Kong, Lingyang;Hartnagel, Timothy J.;Carpino, Carly A.;Gee, Stephen E.;Picarello, Danielle M.;Rubin, Amanda S.;Lee, Jumin;Park, Soohyung
通讯作者：
Park, Soohyung

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications.