Using Structural Systems Biology Modelling to Probe High-Resolution Design Principles of Protein Networks

利用结构系统生物学模型探索蛋白质网络的高分辨率设计原理

• 批准号: RGPIN-2019-05952
• 负责人: Xia, Yu
• 金额: $ 3.64万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738616
• 关键词: Using; Structural; Systems; Biology; Modelling; Using; Structural; Systems; Biology; Modelling

Systems biology aims to build a working model of the cell by first mapping the network of interactions among biomolecules in the cell. While highly successful, this network-based view of the cell often treats biomolecules and their interactions as nodes and edges with little atomic details. Such details are crucial because atomic-level changes in the molecular circuitry can lead to large differences in cell behaviour, as often happens in evolution, development, and regulation. Specifically addressing this urgent need, the proposed research program focuses on the application of high-resolution structural modelling to systems biology ("structural systems biology"). Supported by the previous NSERC Discovery Grant, we have developed template-based homology modelling methods to build accurate structural models of nodes and edges within experimentally-determined protein-protein interaction networks ("interactomes"). In addition, we have used these structural models to elucidate high-resolution design principles of interactome networks that are otherwise hidden in the traditional binary network. In the last five years, we have successfully applied this structural systems biology approach to address numerous fundamental questions in molecular and network evolution, interspecies interactions, and alternative splicing. In the next five years, we will apply such structural systems biology approaches to address a range of new fundamental questions in molecular biophysics, genetics, and evolution, in order to elucidate new high-resolution design principles of interactome networks. Three short-term objectives are proposed. First, we will use structural systems biology to calculate the fraction of protein-protein interactions in the cell that are neutral upon perturbation. Second, we will use structural systems biology to quantitatively elucidate structural determinants of protein-protein interaction evolution at the residue level. Third, we will use structural systems biology to quantitatively elucidate structural determinants of enzyme evolution at the residue level. The proposed research program integrates methodology development in structural systems biology with fundamental applications, and represents the most comprehensive effort to elucidate high-resolution design principles of interactome networks. These quantitative insights can in turn be used to guide current efforts in enzyme engineering, protein engineering, and synthetic biology. In the long term, the proposed research program will build a multi-scale model of the cell circuitry, where the causes at the atomic level and the consequences at the organismal level can be modelled together in a unified framework. Such a multi-scale model of the cell is essential for transforming molecular cell biology into a predictive science, as well as for enabling rational design in biomolecular and cellular engineering.

系统生物学旨在通过首先映射细胞中生物分子之间的相互作用网络来构建细胞的工作模型。尽管非常成功，但这种基于网络的细胞观点通常将生物分子及其相互作用视为节点和边缘，而原子质细节很少。这样的细节至关重要，因为分子回路的原子级变化会导致细胞行为的巨大差异，因为进化，发育和调节经常发生。拟议的研究计划特别针对这种迫切需求，重点是将高分辨率结构建模应用于系统生物学（“结构系统生物学”）。在先前的NSERC Discovery Grant支持下，我们开发了基于模板的同源性建模方法，以在实验性确定的蛋白质 - 蛋白质相互作用网络（“ Interactomes”）中构建节点和边缘的准确结构模型。此外，我们还使用了这些结构模型来阐明传统二进制网络中隐藏的Interactome网络的高分辨率设计原理。在过去的五年中，我们成功地应用了这种结构系统生物学方法来解决分子和网络进化，种间相互作用和替代剪接方面的众多基本问题。在接下来的五年中，我们将采用这种结构系统生物学方法来解决分子生物物理学，遗传学和进化中的一系列新的基本问题，以阐明相互作用网络的新高分辨率设计原理。提出了三个短期目标。首先，我们将使用结构系统生物学来计算细胞中蛋白质 - 蛋白质相互作用在扰动时处于中立的比例。其次，我们将使用结构系统生物学来定量阐明残基水平蛋白质蛋白相互作用演化的结构决定因素。第三，我们将使用结构系统生物学来定量阐明残基水平的酶进化的结构决定因素。拟议的研究计划将结构系统生物学中的方法开发与基本应用相结合，并代表了阐明Interactome网络的高分辨率设计原理的最全面的努力。这些定量见解反过来又可以用来指导当前在酶工程，蛋白质工程和合成生物学方面的努力。从长远来看，拟议的研究计划将建立一个多尺度模型的细胞电路模型，该模型在原子水平上的原因，并且可以在统一的框架中一起建模有机水平的后果。这种细胞的多尺度模型对于将分子细胞生物学转化为预测科学以及在生物分子和细胞工程中的理性设计至关重要。