Ensemble Kinetic Modeling of Metabolic Networks from Dynamic Metabolic Profiles.docVIP

Metabolites 2012, 2, 891-912; doi:10.3390/metabo2040891 OPEN ACCESS metabolites ISSN 2218-1989 /journal/metabolites/ Article Ensemble Kinetic Modeling of Metabolic Networks from Dynamic Metabolic Profiles Gengjie Jia 1, Gregory Stephanopoulos 2 and Rudiyanto Gunawan 3,* 1 Chemical and Pharmaceutical Engineering, Singapore-MIT Alliance, Singapore 117576;, Singapore; E-Mail: jiagengjie@.sg (G.J.) 2 Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; E-Mail: gregstep@ (G.S.) 3 Institute for Chemical and Bioengineering, ETH Zurich, 8093 Zurich, Switzerland * Author to whom correspondence should be addressed; E-Mail: rudi.gunawan@chem.ethz.ch; Tel.: +41 44 633 21 34; Fax: +41 44 633 12 52. Received: 14 September 2012; in revised form: 2 November 2012 / Accepted: 5 November 2012 / Published: 12 November 2012 Abstract: Kinetic modeling of metabolic pathways has important applications in metabolic engineering, but significant challenges still remain. The difficulties faced vary from finding best-fit parameters in a highly multidimensional search space to incomplete parameter identifiability. To meet some of these challenges, an ensemble modeling method is developed for characterizing a subset of kinetic parameters that give statistically equivalent goodness-of-fit to time series concentration data. The method is based on the incremental identification approach, where the parameter estimation is done in a step-wise manner. Numerical efficacy is achieved by reducing the dimensionality of parameter space and using efficient random parameter exploration algorithms. The shift toward using model ensembles, instead of the traditional “best-fit” models, is necessary to directly account for model uncertainty during the application of such models. The performance of the ensemble modeling approach has been demonstrated in the modeling of a generic branched pathway and the