Reusable rule-based cell cycle model explains compartment-resolved dynamics of 16 observables in RPE-1 cells

The mammalian cell cycle is regulated by a well-studied but complex biochemical reaction system. Computational models provide a particularly systematic and systemic description of the mechanisms governing mammalian cell cycle control. By combining both state-of-the-art multiplexed experimental methods and powerful computational tools, this work aims at improving on these models along four dimensions: model structure, validation data, validation methodology and model reusability.We developed a comprehensive model structure of the full cell cycle that qualitatively explains the behaviour of human retinal pigment epithelial-1 cells. To estimate the model parameters, time courses of eight cell cycle regulators in two compartments were reconstructed from single cell snapshot measurements. After optimisation with a parallel global optimisation metaheuristic we obtained excellent agreements between simulations and measurements. The PEtab specification of the optimisation problem facilitates reuse of model, data and/or optimisation results.Future perturbation experiments will improve parameter identifiability and allow for testing model predictive power. Such a predictive model may aid in drug discovery for cell cycle-related disorders.Author summary: While there are numerous cell cycle models in the literature, mammalian cell cycle models typically suffer from four limitations. Firstly, the descriptions of biological mechanisms are often inefficiently complicated yet insufficiently comprehensive and detailed. Secondly, there is a lack of experimental data to validate the model. Thirdly, inadequate parameter estimation procedures are used. Lastly, there is no standardized description of the model and/or optimization problem.