StressME: unified computing framework ofEscherichia colimetabolism, gene expression, and stress responses

Abstract Generalist microbes have adapted to a multitude of environmental stresses through their integrated stress response system. Individual stress responses have been quantified by E. coli metabolism and expression (ME) models under thermal, oxidative and acid stress, respectively. However, the systematic quantification of crosstalk among these stress responses remains lacking. Here, we present StressME: the unified stress response model of E. coli combining thermal (FoldME), oxidative (OxidizeME) and acid (AcidifyME) stress responses. StressME is the most up to date ME model for E. coli and it reproduces all published single-stress ME models. Additionally, it includes refined rate constants to improve prediction accuracy for wild-type and stress-evolved strains. StressME revealed certain optimal proteome allocation strategies associated with cross-stress responses. These stress-optimal proteomes were shaped by trade-offs between protective vs. metabolic enzymes; cytoplasmic vs. periplasmic chaperones; and expression of stress-specific proteins. As StressME is tuned to compute metabolic and gene expression responses under mild acid, oxidative, and thermal stresses, it is useful for engineering and health applications. The modular design of our open-source package also facilitates model expansion (e.g., to new stress mechanisms) by the computational biology community. Author summary A fundamental understanding of multi-stress adaptation in E.coli has potential industrial relevance. While individual stress responses have been quantified through the protein regulatory network in E.coli , the systematic quantification of the crosstalk among stress responses remains lacking. Here, we develop a new modeling pipeline by which thermal, oxidative and acid stress response can be coupled to each other, and the metabolic activities, protein and metabolic flux redistribution due to cross stress can be quantified. We optimize the effective rate constants in the integrated model. We then confirm the model robustness by validating against the published data under single stress. Finally, we use the model to characterize the cross-adaptation between protective and catalytic proteins as well as between chaperones present in different cellular compartments. We find effective cross-protection against cross stress by adapting the E.coli cells to the thermal stress first. We also indicate the presence of trade-offs by which the cell may refuse to give up more protein allocation away from one stress response to the other, because doing so would decrease stress tolerance further. The single stress plug-in design makes the model build-up pipeline flexible and expandable, allowing incorporation of more stressors into the model architecture for industrial applications.