Non-linear optimization of biochemical pathways: applications to metabolicengineering and parameter estimation

Motivation: The simulation of biochemical kinetic systems is a powerful app roach that can be used for: (i) checking the consistency of a postulated mo del with a set of experimental measurements, (ii) answering 'what if?' ques tions and (iii) exploring possible behaviours of a model. Here we describe a generic approach to combine numerical optimization methods with biochemic al kinetic simulations, which is suitable for use in the rational design of improved metabolic pathways with industrial significance (metabolic engine ering) and for solving the inverse problem of metabolic pathways, i.e. the estimation of parameters from measured variables. Results: We discuss the suitability, of various optimization methods, focus ing especially on their ability, or otherwise to find global optima. We rec ommend that a suite of diverse optimization methods should be available in simulation software as no single one performs best for all problems. We des cribe how we have implemented such a simulation-optimization strategy in th e biochemical kinetics simulator Gepasi and present examples of its applica tion.