DynamicME: Dynamic simulation and refinement of integrated models of metabolism and protein expression

Abstract

Background: Genome-scale models of metabolism and macromolecular expression (ME models) enable systems-level computation of proteome allocation coupled to metabolic phenotype. Results: We develop DynamicME, an algorithm enabling time-course simulation of cell metabolism and protein expression. DynamicME correctly predicted the substrate utilization hierarchy on a mixed carbon substrate medium. We also found good agreement between predicted and measured time-course expression profiles. ME models involve considerably more parameters than metabolic models (M models). We thus generate an ensemble of models (each model having its rate constants perturbed), and then analyze the models by identifying archetypal time-course metabolite concentration profiles. Furthermore, we use a metaheuristic optimization method to calibrate ME model parameters using time-course measurements such as from a (fed-) batch culture. Finally, we show that constraints on protein concentration dynamics ("inertia") alter the metabolic response to environmental fluctuations, including increased substrate-level phosphorylation and lowered oxidative phosphorylation. Conclusions: Overall, DynamicME provides a novel method for understanding proteome allocation and metabolism under complex and transient environments, and to utilize time-course cell culture data for model-based interpretation or model refinement.