Computational and Systems Biology

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，加拿大计算与系统生物学研究主席的拟议研究计划旨在构建精确的，基因组规模的，原子分辨率的三维结构模型，用于模型真核生物物种，人类以及宿主和病原体之间的蛋白质-蛋白质相互作用网络中的节点和边缘。这是通过开发用于高分辨率结构系统生物学的关键使能计算技术以及与领先的实验系统生物学家合作来实现的。这些细胞回路的高分辨率结构模型将用于探索物种内和物种间生物网络的进化和设计原理，并阐明人类传染病和遗传疾病的系统水平机制。拟议的研究计划将结构系统生物学的方法学发展与分子生物物理学，遗传学，进化，生态学和疾病的广泛基础应用相结合，并且代表了阐明相互作用体网络的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蛋白质工程、合成生物学以及包括COVID-19在内的遗传和传染病治疗方面的努力。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 of the Canada Research Chair in Computational and Systems Biology aims to construct accurate, genome-scale, atomic-resolution three-dimensional structural models for nodes and edges within protein-protein interaction networks in model eukaryotic species, in human, and between host and pathogen. This is achieved by developing key enabling computational technologies for high-resolution structural systems biology, and by collaborating with leading experimental systems biologists. These high-resolution structural models of the cell circuitry will then be used to probe evolutionary and design principles of biological networks within and between species, and to elucidate systems-level mechanisms of both human infectious and genetic diseases.The proposed research program integrates methodology development in structural systems biology with a wide range of fundamental applications in molecular biophysics, genetics, evolution, ecology, and disease, 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 protein engineering, synthetic biology, and treatment for genetic and infectious diseases, including COVID-19. 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.