Process System Engineering Laboratory, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Biotechnol Bioeng. 2013 Mar;110(3):792-802. doi: 10.1002/bit.24748. Epub 2012 Oct 18.
Dynamic flux balance analysis (DFBA) provides a platform for detailed design, control and optimization of biochemical process technologies. It is a promising modeling framework that combines genome-scale metabolic network analysis with dynamic simulation of the extracellular environment. Dynamic flux balance analysis assumes that the intracellular species concentrations are in equilibrium with the extracellular environment. The resulting underdetermined stoichiometric model is solved under the assumption of a biochemical objective such as growth rate maximization. The model of the metabolism is coupled with the dynamic mass balance equations of the extracellular environment via expressions for the rates of substrate uptake and product excretion, which imposes additional constraints on the linear program (LP) defined by growth rate maximization of the metabolism. The linear program is embedded into the dynamic model of the bioreactor, and together with the additional constraints this provides an accurate model of the substrate consumption, product secretion, and biomass production during operation. A DFBA model consists of a system of ordinary differential equations for which the evaluation of the right-hand side requires not only function evaluations, but also the solution of one or more linear programs. The numerical tool presented here accurately and efficiently simulates large-scale dynamic flux balance models. The main advantages that this approach has over existing implementation are that the integration scheme has a variable step size, that the linear program only has to be solved when qualitative changes in the optimal flux distribution of the metabolic network occur, and that it can reliably simulate behavior near the boundary of the domain where the model is defined. This is illustrated through large-scale examples taken from the literature.
动态通量平衡分析（DFBA）为生化过程技术的详细设计、控制和优化提供了一个平台。它是一种很有前途的建模框架，将基因组规模的代谢网络分析与细胞外环境的动态模拟相结合。动态通量平衡分析假设细胞内物质浓度与细胞外环境处于平衡状态。在生化目标（如最大生长速率）的假设下，解决由此产生的欠定计量模型。代谢模型与细胞外环境的动态质量平衡方程通过基质摄取和产物排泄速率的表达式耦合，这对代谢物最大生长速率定义的线性规划（LP）施加了额外的约束。线性规划被嵌入到生物反应器的动态模型中，与额外的约束一起，这为操作过程中的基质消耗、产物分泌和生物量生产提供了一个准确的模型。DFBA 模型由一个常微分方程组组成，其右手边的评估不仅需要函数评估，还需要求解一个或多个线性规划。这里提出的数值工具能够准确有效地模拟大规模动态通量平衡模型。与现有实现相比，该方法的主要优势在于积分方案具有可变步长，仅当代谢网络的最优通量分布发生定性变化时才需要求解线性规划，并且可以可靠地模拟模型定义域边界附近的行为。通过来自文献的大规模示例来说明这一点。
