A global resource allocation strategy governs growth transition kinetics of Escherichia coli

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Abstract

A new approach to modelling bacterial growth removes the need to know kinetic parameters for metabolic and regulatory processes and can be used to model adaptive processes such as antibiotic responses and ecological dynamics.

A grand challenge of systems biology is to predict the kinetic responses of living systems to perturbations starting from the underlying molecular interactions. Changes in the nutrient environment have long been used to study regulation and adaptation phenomena in microorganisms1,2,3 and they remain a topic of active investigation4,5,6,7,8,9,10,11. Although much is known about the molecular interactions that govern the regulation of key metabolic processes in response to applied perturbations12,13,14,15,16,17, they are insufficiently quantified for predictive bottom-up modelling. Here we develop a top-down approach, expanding the recently established coarse-grained proteome allocation models15,18,19,20 from steady-state growth into the kinetic regime. Using only qualitative knowledge of the underlying regulatory processes and imposing the condition of flux balance, we derive a quantitative model of bacterial growth transitions that is independent of inaccessible kinetic parameters. The resulting flux-controlled regulation model accurately predicts the time course of gene expression and biomass accumulation in response to carbon upshifts and downshifts (for example, diauxic shifts) without adjustable parameters. As predicted by the model and validated by quantitative proteomics, cells exhibit suboptimal recovery kinetics in response to nutrient shifts owing to a rigid strategy of protein synthesis allocation, which is not directed towards alleviating specific metabolic bottlenecks. Our approach does not rely on kinetic parameters, and therefore points to a theoretical framework for describing a broad range of such kinetic processes without detailed knowledge of the underlying biochemical reactions.

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