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IIBR Informatics: Tools and databases for proteome-wide modeling and analysis of alpha-helix association in membrane, from folding intermediates to structural interactomes

IIBR 信息学：用于全蛋白质组建模和膜中 α 螺旋关联分析（从折叠中间体到结构相互作用组）的工具和数据库

基本信息

批准号：
1855425
负责人：
Andrei Lomize
金额：
$ 79.5万
依托单位：
Regents of the University of Michigan - Ann Arbor
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1855425&HistoricalAwards=false
关键词：
IIBR Informatics Tools databases proteome

项目摘要

Single-pass (i.e. bitopic) transmembrane (TM) proteins are the most abundant and functionally diverse, but the least explored class of eukaryotic membrane proteins. Bitopic receptors, enzymes, adhesion proteins, and transcription regulators play key roles in many vital processes, including cell growth, proliferation, differentiation, migration, communication, apoptosis, and malignant transformation. To perform their biological functions, these proteins form dimers or larger complexes via their TM alpha-helices and water-soluble domains. The high flexibility and structural heterogeneity of alpha-helical complexes in membranes impede their crystallization and require development of computational approaches as a viable alternative to obtain three-dimensional (3D) structures and multistate organization of TM complexes. The current project aims to develop and apply new computational methods to solve the problem of modeling TM heterodimers of bitopic proteins, enabling proteome-wide studies of their structures. The developed methodology, tools, and complementary databases will advance ab initio protein structure prediction methods, which will benefit a broad community of researchers, teachers, and students who work or study in the fields of biophysics, structural and evolutionary biology, medicinal chemistry, and bioinformatics. Through its broader impacts, this project offers an opportunity to train undergraduate and graduate computer science students in developing bioinformatics resources using new computer languages and web technologies. The developed toolbox will be used in the curriculum for a graduate-level medicinal chemistry course and web-based workshops. Further, the project will support the biology education in an Oklahoma City public school with a high percentage of underrepresented minority students. The project will generate a novel computational infrastructure composed of two databases and five web tools. Three methods and web tools will be newly developed: (1) TMmatch for the identification and modeling of TM heterodimers; (2) TMPfold for the detection and analysis of stable two-helical folding units in 3D structures of membrane proteins; and (3) 1TMnet for the visualization of protein interaction networks in membranes. These web tools will be included in two improved databases together with the existing PPM and FMAP auxiliary web servers for modeling and positioning of alpha-helices in membranes. The expanded Membranome database, which collects bitopic proteins from six organisms, will incorporate 3D structures of all TM dimers modeled by TMmatch and protein networks identified by 1TMnet (https://membranome.org/ ). The upgraded OPM database, which holds all membrane proteins with known 3D structures positioned in membranes, will include structures of stable two-helical folding units detected by TMPfold and TMmatch in integral membrane proteins (https://opm.phar.umich.edu/). The proposed toolbox will allow for the creation of a scientific workflow from proteome-wide modeling of bitopic protein TM dimers to identification of their interaction networks associated with various biological pathways in different cells and organisms. The comparison of interaction maps of bitopic proteins from six selected species representing all kingdoms of life will advance our knowledge of increased biocomplexity of single-pass membrane proteins during evolution. The easy-to use public web tools will be beneficial for academic and health-related research. The TMPfold web tool will enable computational determination of stable alpha-helical folding intermediates, thus paving the way to ab-initio modeling of structures of multi-pass membrane proteins and analysis of their folding pathways. The TMmatch web server will enable analysis of structural effects of disease-related mutations in TM dimers and will help in the design and optimization of TM alpha-helical complexes for therapeutic purposes.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.

单程（即双位）跨膜 (TM) 蛋白是最丰富、功能多样、但研究最少的一类真核膜蛋白。双位受体、酶、粘附蛋白和转录调节因子在许多重要过程中发挥关键作用，包括细胞生长、增殖、分化、迁移、通讯、凋亡和恶性转化。为了发挥其生物学功能，这些蛋白质通过其 TM α 螺旋和水溶性结构域形成二聚体或更大的复合物。膜中α螺旋复合物的高灵活性和结构异质性阻碍了它们的结晶，需要开发计算方法作为获得TM复合物的三维（3D）结构和多态组织的可行替代方案。当前的项目旨在开发和应用新的计算方法来解决双位蛋白 TM 异二聚体的建模问题，从而能够对其结构进行蛋白质组范围的研究。所开发的方法、工具和补充数据库将推进从头开始的蛋白质结构预测方法，这将使在生物物理学、结构和进化生物学、药物化学和生物信息学领域工作或学习的广大研究人员、教师和学生受益。通过其更广泛的影响，该项目为培训计算机科学本科生和研究生使用新的计算机语言和网络技术开发生物信息学资源提供了机会。开发的工具箱将用于研究生水平药物化学课程和网络研讨会的课程中。此外，该项目还将支持俄克拉荷马城一所公立学校的生物教育，该学校的少数族裔学生比例很高。该项目将生成一个新颖的计算基础设施，由两个数据库和五个网络工具组成。将新开发三种方法和网络工具：（1）TMmatch，用于TM异二聚体的识别和建模； (2) TMPfold，用于检测和分析膜蛋白3D结构中稳定的双螺旋折叠单元； (3) 1TMnet 用于膜中蛋白质相互作用网络的可视化。这些网络工具将与现有的 PPM 和 FMAP 辅助网络服务器一起包含在两个改进的数据库中，用于膜中 α 螺旋的建模和定位。扩展的膜组数据库收集了来自六种生物体的双位蛋白，将纳入由 TMmatch 建模的所有 TM 二聚体的 3D 结构以及由 1TMnet (https://membranome.org/ ) 识别的蛋白质网络。升级后的 OPM 数据库包含膜中已知 3D 结构的所有膜蛋白，将包括通过 TMPfold 和 TMmatch 在完整膜蛋白中检测到的稳定双螺旋折叠单元的结构 (https://opm.phar.umich.edu/)。所提出的工具箱将允许创建一个科学工作流程，从双位蛋白TM二聚体的全蛋白质组建模到识别与不同细胞和生物体中的各种生物途径相关的相互作用网络。对代表所有生命王国的六个选定物种的双位蛋白相互作用图进行比较，将增进我们对单程膜蛋白在进化过程中生物复杂性增加的认识。易于使用的公共网络工具将有利于学术和健康相关的研究。 TMPfold 网络工具将能够通过计算确定稳定的 α 螺旋折叠中间体，从而为多通道膜蛋白结构的从头建模及其折叠途径分析铺平道路。 TMmatch 网络服务器将能够分析 TM 二聚体中与疾病相关的突变的结构效应，并将有助于设计和优化用于治疗目的的 TM α-螺旋复合物。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。