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

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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.