Pathway identification using parallel optimization for a complex metabolic system in microbial continuous culture

The bio-dissimilation of glycerol to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae (K. pneumoniae) is a complex bioprocess due to the multiple inhibitions of substrate and products onto the cell growth. In consideration of the fact that both the inhibition mechanisms of 3-hydroxypropionaldehyde (3-HPA) onto the cell growth and the transport systems of glycerol and 1,3-PD across the cell membrane are still unclear, we consider 72 possible metabolic pathways, and establish a novel mathematical model which is represented by an eight-dimensional nonlinear dynamical system. The existence, uniqueness, continuous dependence of solutions to the system and the compactness of the solution set are explored. On the basis of biological robustness, we give a quantitative definition of robustness index of the intracellular substances. Taking the robustness index of the intracellular substances together with the relative error between the experimental data and the computational values of the extracellular substances as a performance index, a parameter identification model is proposed for the nonlinear dynamical system, in which 43848 continuous variables and 1152 discrete variables are involved. A parallel particle swarm optimization — pathways identification algorithm (PPSO-PIA) is constructed to find the optimal pathway and parameters under various experiments conditions. Numerical results show that the optimal pathway and the corresponding dynamical system can describe the continuous fermentation reasonably.     

Complex metabolic network of glycerol fermentation by Klebsiella pneumoniae and its system identification via biological robustness

The bioconversion of glycerol to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae (K. pneumoniae) can be characterized by an intricate metabolic network of interactions among biochemical fluxes, metabolic compounds, key enzymes and genetic regulation. Since there are some uncertain factors in the fermentation, especially the transport mechanisms of substances across cell membrane, the metabolic network contains multiple possible metabolic systems. In this paper, we establish a complex metabolic network and the corresponding nonlinear hybrid dynamical system aiming to determine the most possible metabolic system. The existence, uniqueness and continuity of solutions are discussed. We quantitatively describe biological robustness and present a system identification model on the basis of robustness performance. The identification problem is decomposed into two subproblems and a procedure is constructed to solve them. Numerical results show that it is most possible that both glycerol and 1,3-PD pass the cell membrane by active transport coupling with passive diffusion under substrate-sufficient conditions, whereas, under substrate-limited conditions, glycerol passes cell membrane by active transport coupling with passive diffusion and 1,3-PD by active transport.     

Optimal switching control of a fed-batch fermentation process

Considering the hybrid nature in fed-batch culture of glycerol biconversion to 1,3-propanediol (1,3-PD) by Klebsiella pneumoniae, we propose a state-based switching dynamical system to describe the fermentation process. To maximize the concentration of 1,3-PD at the terminal time, an optimal switching control model subject to our proposed switching system and constraints of continuous state inequality and control function is presented. Because the number of the switchings is not known a priori, we reformulate the above optimal control problem as a two-level optimization problem. An optimization algorithm is developed to seek the optimal solution on the basis of a heuristic approach and control parametrization technique. Numerical results show that, by employing the obtained optimal control strategy, 1,3-PD concentration at the terminal time can be increased considerably.     

Sensitivity analysis and identification of kinetic parameters in batch fermentation of glycerol

A nonlinear dynamical system was established in our preceding work to describe the batch and continuous bioconversions of glycerol to 1,3-propanediol by Klebsiella pneumoniae. The purpose of this article is to analyze the sensitivity of kinetic parameters of the dynamical system and identify their values from experiment. A global sensitivity analysis approach is constructed by combining the local technique with the Monte Carlo method. With only those parameters of higher sensitivity as design variables, we propose a parameter identification model and solve it by a gradient-based simulated annealing algorithm. Numerical results show that our methods are feasible and efficient.     

Discrete optimal control model and bound error for microbial continuous fermentation

A discrete optimal control model is given according to the discrete nonlinear dynamic system of continuous fermentations of glycerol to 1,3-propanediol (1,3-PD). The property of some major functions and their bounds on approximation errors are studied in this paper. Then, the conclusion that the optimality function of discrete optimal control model is the consistent approximation to one of the continuous optimal control model is proved. The results presented in this work can be used as guidelines for the optimal algorithm and its convergence.     

Bilevel parameters identification for the multi-stage nonlinear impulsive system in microorganisms fed-batch cultures

Considering the abrupt jump of the substrate and different characters of the bacterial in the lag phase, the exponential phase and the stationary phase this paper proposes the multi-stage nonlinear impulsive system for the fed-batch fermentation from glycerol to 1,3-propanediol (1,3-PD) and establishes the bilevel identification system for its sensitive parameters. The properties of the solutions for the nonlinear multi-stage dynamical system are investigated and identifiability of the parameters is proved. Finally an optimal algorithm is constructed to obtain the optimal solution of the identification model and the numerical example is then discussed to illustrate the algorithm.