Modeling the temporal dynamics of master regulators and CtrA proteolysis in Caulobacter crescentus cell cycle

Abstract

The cell cycle of Caulobacter crescentus involves the polar morphogenesis and an asymmetric cell division driven by precise interactions and regulations of proteins, which makes Caulobacter an ideal model organism for investigating bacterial cell development and differentiation. The abundance of molecular data accumulated on Caulobacter motivates system biologists to analyze the complex regulatory network of cell cycle via quantitative modeling. In this paper, We propose a comprehensive model to accurately characterize the underlying mechanisms of cell cycle regulation based on the study of: a) chromosome replication and methylation; b) interactive pathways of five master regulatory proteins including DnaA, GcrA, CcrM, CtrA, and SciP, as well as novel consideration of their corresponding mRNAs; c) cell cycle-dependent proteolysis of CtrA through hierarchical protease complexes. The temporal dynamics of our simulation results are able to closely replicate an extensive set of experimental observations and capture the main phenotype of seven mutant strains of Caulobacter crescentus. Collectively, the proposed model can be used to predict phenotypes of other mutant cases, especially for nonviable strains which are hard to cultivate and observe. Moreover, the module of cyclic proteolysis is an efficient tool to study the metabolism of proteins with similar mechanisms.

Design patterns for the construction of computational biological models

“…Computational models are among the well-known tools that systems biologists employ to study the interactions between different biological components at the system level [ 1–4 ]. These mechanistic models can be constructed to simulate temporal and/or spatial dynamics of a network of reactions [ 5 ], a complete cell [ 6 ] or a holistic model of multi-cells [ 7 ]. Computational biological models consist of two main building blocks: model structure and model parameters [ 8 ].…”