Advanced Modeling of Cellular Proliferation: Toward a Multi-scale Framework Coupling Cell Cycle to Metabolism by Integrating Logical and Constraint-Based Models

Biological functions require a coherent cross talk among multiple layers of regulation within the cell. Computational efforts that aim to understand how these layers are integrated across spatial, temporal, and functional scales represent a challenge in Systems Biology. We have developed a computational, multi-scale framework that couples cell cycle and metabolism networks in the budding yeast cell. Here we describe the methodology at the basis of this framework, which integrates on off-the-shelf logical (Boolean) models of a minimal yeast cell cycle with a constraint-based model of metabolism (i.e., the Yeast 7 metabolic network reconstruction). Models are implemented in Python code using the BooleanNet and COBRApy packages, respectively, and are connected through the Boolean logic. The methodology allows for incorporation of interaction data, and validation through –omics data. Furthermore, evolutionary strategies may be incorporated to explore regulatory structures underlying coherent cross talks among regulatory layers.