Perfect Adaptation and Optimal Equilibrium Productivity in a Simple Microbial Biofuel Metabolic Pathway Using Dynamic Integral Control.

The production of complex biomolecules by genetically engineered organisms is one of the most promising applications of metabolic engineering and synthetic biology. To obtain processes with high productivity, it is therefore crucial to design and implement efficient dynamic in vivo regulation strategies. We consider here the microbial biofuel production model of Dunlop et al. (2010) for which we demonstrate that an antithetic dynamic integral control strategy can achieve robust perfect adaptation for the intracellular biofuel concentration in the presence of poorly known network parameters and implementation errors in certain rate parameters of the controller. We also show that the maximum equilibrium extracellular biofuel productivity is fully defined by some of the network parameters and, in this respect, it can only be achieved when all the corresponding parameters are perfectly known. Since this optimum is a network property, it cannot be improved by the use of any controller that measures the intracellular biofuel concentration and acts on the production of pump proteins. Additional intrinsic fundamental properties for the process are also unveiled, the most important ones being the existence of a conservation relation between the productivity and the toxicity, a low sensitivity of the optimal productivity with respect to a poor implementation of the set-point for the intracellular biofuel, and a strong intrinsic robustness property of the optimal productivity with respect to poorly known parameters. Taken together, these results demonstrate that a high and robust equilibrium rate of production for the extracellular biofuel can be achieved when the parameters of the model are poorly known and those of the controllers are poorly implemented. Finally, several advantages of the proposed dynamic strategy over a static one are also emphasized.