Using dynamic perturbations to identify fragilities in biochemical networks

Abstract

AbstractBiological functions at the cellular level result from interactions between genes, proteins and metabolites within complex biochemical reaction networks. Identifying specific and localized fragilities in such networks is important to understand the source of biological malfunctions, and to devise strategies for fighting disease states that have developed robustness. Herein we consider a method based on robust control theoretic concepts for identifying network fragilities. In particular, we consider adding static or dynamic perturbations to the network edges, i.e. the direct binary interactions within the network, and compute the smallest perturbation that induces a bifurcation, and hence a qualitative change, in the network function. The proposed method can also serve as a powerful modeling tool in that it can be used to identify parts of a model that require more detailed descriptions of the underlying processes. The method is demonstrated by application to models of sustained oscillations in the glycolytic pathway and bistability in the mitogen‐activated protein kinase (MAPK) signal transduction. Copyright © 2010 John Wiley & Sons, Ltd.