Constructing kinetic models of metabolism at genome‐scales: A review

Abstract Constraint‐based modeling of biological networks (metabolism, transcription and signal transduction), although used successfully in many applications, suffer from specific limitations such as the lack of representation of metabolite concentrations and enzymatic regulation, which are necessary for a complete physiologically relevant model. Kinetic models conversely overcome these shortcomings and enable dynamic analysis of biological systems for enhanced in silico hypothesis generation. Nonetheless, kinetic models also have limitations for modeling at genome‐scales chiefly due to: (i) model non‐linearity; (ii) computational tractability; (iii) parameter identifiability; (iv) estimability; and (v) uncertainty. In order to support further development of kinetic models as viable alternatives to constraint‐based models, this review presents a brief description of the existing obstacles towards building genome‐scale kinetic models. Specific kinetic modeling frameworks capable of overcoming these obstacles are covered in this review. The tractability and physiological feasibility of these models are discussed with the objective of using available in vivo experimental observations to define the model parameter space. Among the different methods discussed, Monte Carlo kinetic models of metabolism stand out as potentially tractable methods to model genome scale networks while also addressing in vivo parameter uncertainty.