Dynamical Allocation of Cellular Resources as an Optimal Control Problem: Novel Insights into Microbial Growth Strategies

Microbial physiology exhibits growth laws that relate the macromolecular composition of the cell to the growth rate. Recent work has shown that these empirical regularities can be derived from coarse-grained models of resource allocation. While these studies focus on steady-state growth, such conditions are rarely found in natural habitats, where microorganisms are continually challenged by environmental fluctuations. The aim of this paper is to extend the study of microbial growth strategies to dynamical environments, using a self-replicator model. We formulate dynamical growth maximization as an optimal control problem that can be solved using Pontryagin’s Maximum Principle. We compare this theoretical gold standard with different possible implementations of growth control in bacterial cells. We find that simple control strategies enabling growth-rate maximization at steady state are suboptimal for transitions from one growth regime to another, for example when shifting bacterial cells to a medium supporting a higher growth rate. A near-optimal control strategy in dynamical conditions is shown to require information on several, rather than a single physiological variable. Interestingly, this strategy has structural analogies with the regulation of ribosomal protein synthesis by ppGpp in the enterobacterium Escherichia coli. It involves sensing a mismatch between precursor and ribosome concentrations, as well as the adjustment of ribosome synthesis in a switch-like manner. Our results show how the capability of regulatory systems to integrate information about several physiological variables is critical for optimizing growth in a changing environment.Author Summary: Microbial growth is the process by which cells sustain and reproduce themselves from available matter and energy. Strategies enabling microorganisms to optimize their growth rate have been extensively studied, but mostly in stable environments. Here, we build a coarse-grained model of microbial growth and use methods from optimal control theory to determine a resource allocation scheme that would lead to maximal biomass accumulation when the cells are dynamically shifted from one growth medium to another. We compare this optimal solution with several cellular implementations of growth control, based on the capacity of the cell to sense different physiological variables. We find that strategies maximizing growth in steady-state conditions perform quite differently in dynamical conditions. Moreover, the control strategy with performance close to the theoretical maximum exploits information of more than one physiological variable, suggesting that optimization of microbial growth in dynamical rather than steady environments requires broader sensory capacities. Interestingly, the ppGpp alarmone system in the enterobacterium Escherichia coli, known to play an important role in growth control, has structural similarities with the control strategy approaching the theoretical maximum. It senses a discrepancy between the concentrations of precursors and ribosomes, and adjusts ribosome synthesis in an on-off fashion. This suggests that E. coli is adapted for environments with intermittent, rapid changes in nutrient availability.