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Using the Topology of Metabolic Networks to Predict Viability of Mutant Strains

Zeba Wunderlich ^* and Leonid A. Mirny 

^* Biophysics Program, Harvard University, Cambridge, Massachusetts; and Harvard-MIT Division of Health Sciences and Technology, Cambridge, Massachusetts

Correspondence: Address reprint requests to Leonid Mirny, Harvard-MIT Div. of Health Sciences & Technology, Massachusetts Institute of Technology, 77 Massachusetts Ave., Cambridge, MA 02139. Tel.: 617-452-4862; Fax: 617-253-2514; E-mail: leonid{at}mit.edu.

Understanding the relationships between the structure (topology) and function of biological networks is a central question of systems biology. The idea that topology is a major determinant of systems function has become an attractive and highly disputed hypothesis. Although structural analysis of interaction networks demonstrates a correlation between the topological properties of a node (protein, gene) in the network and its functional essentiality, the analysis of metabolic networks fails to find such correlations. In contrast, approaches utilizing both the topology and biochemical parameters of metabolic networks, e.g., flux balance analysis, are more successful in predicting phenotypes of knockout strains. We reconcile these seemingly conflicting results by showing that the topology of the metabolic networks of both Escherichia coli and Saccharomyces cerevisiae are, in fact, sufficient to predict the viability of knockout strains with accuracy comparable to flux balance analysis on large, unbiased mutant data sets. This surprising result is obtained by introducing a novel topology-based measure of network transport: synthetic accessibility. We also show that other popular topology-based characteristics such as node degree, graph diameter, and node usage (betweenness) fail to predict the viability of E. coli mutant strains. The success of synthetic accessibility demonstrates its ability to capture the essential properties of the metabolic network, such as the branching of chemical reactions and the directed transport of material from inputs to outputs. Our results strongly support a link between the topology and function of biological networks and, in agreement with recent genetic studies, emphasize the minimal role of flux rerouting in providing robustness of mutant strains.