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

系统生物学旨在通过首先绘制细胞中生物分子之间相互作用的网络来建立细胞的工作模型。虽然非常成功，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，几乎没有原子细节。这些细节至关重要，因为分子电路中原子水平的变化可能导致细胞行为的巨大差异，这在进化，发育和调节中经常发生。具体解决这一迫切需要，拟议的研究计划侧重于高分辨率结构建模系统生物学（“结构系统生物学”）的应用。在先前的NSERC发现资助的支持下，我们开发了基于模板的同源性建模方法，以在实验确定的蛋白质-蛋白质相互作用网络（“相互作用组”）中构建节点和边缘的准确结构模型。此外，我们已经使用这些结构模型来阐明相互作用体网络的高分辨率设计原则，否则隐藏在传统的二进制网络。在过去的五年中，我们已经成功地应用这种结构系统生物学方法来解决分子和网络进化，物种间相互作用和选择性剪接中的许多基本问题。在接下来的五年里，我们将应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，以阐明新的高分辨率设计原则的相互作用网络。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-蛋白质相互作用的比例，这些蛋白质-蛋白质相互作用在扰动时是中性的。其次，我们将使用结构系统生物学定量阐明蛋白质-蛋白质相互作用的结构决定因素在残基水平上的演变。第三，我们将使用结构系统生物学定量阐明酶进化的结构决定因素在残基水平。拟议的研究计划将结构系统生物学的方法学发展与基本应用相结合，并代表了阐明相互作用体网络高分辨率设计原理的最全面的努力。这些定量的见解可以反过来用于指导目前在酶工程，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细胞电路的多尺度模型，其中原子水平的原因和生物体水平的后果可以在一个统一的框架中一起建模。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使生物分子和细胞工程的合理设计成为可能至关重要。

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.