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Computing smallest intervention strategies for multiple metabolic networks in a boolean model.

ABSTRACT: This article considers the problem whereby, given two metabolic networks N1 and N2, a set of source compounds, and a set of target compounds, we must find the minimum set of reactions whose removal (knockout) ensures that the target compounds are not producible in N1 but are producible in N2. Similar studies exist for the problem of finding the minimum knockout with the smallest side effect for a single network. However, if technologies of external perturbations are advanced in the near future, it may be important to develop methods of computing the minimum knockout for multiple networks (MKMN). Flux balance analysis (FBA) is efficient if a well-polished model is available. However, that is not always the case. Therefore, in this article, we study MKMN in Boolean models and an elementary mode (EM)-based model. Integer linear programming (ILP)-based methods are developed for these models, since MKMN is NP-complete for both the Boolean model and the EM-based model. Computer experiments are conducted with metabolic networks of clostridium perfringens SM101 and bifidobacterium longum DJO10A, respectively known as bad bacteria and good bacteria for the human intestine. The results show that larger networks are more likely to have MKMN solutions. However, solving for these larger networks takes a very long time, and often the computation cannot be completed. This is reasonable, because small networks do not have many alternative pathways, making it difficult to satisfy the MKMN condition, whereas in large networks the number of candidate solutions explodes. Our developed software minFvskO is available online.

SUBMITTER: Lu W

PROVIDER: S-EPMC4326032 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Computing smallest intervention strategies for multiple metabolic networks in a boolean model.

Lu Wei W Tamura Takeyuki T Song Jiangning J Akutsu Tatsuya T

Journal of computational biology : a journal of computational molecular cell biology 20150201 2

This article considers the problem whereby, given two metabolic networks N1 and N2, a set of source compounds, and a set of target compounds, we must find the minimum set of reactions whose removal (knockout) ensures that the target compounds are not producible in N1 but are producible in N2. Similar studies exist for the problem of finding the minimum knockout with the smallest side effect for a single network. However, if technologies of external perturbations are advanced in the near future, ...[more]

PMID: 25684199

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Project description:In a gene regulatory network (GRN), gene expressions are affected by noise, and stochastic fluctuations exist in the interactions among genes. These stochastic interactions are context dependent, thus it becomes important to consider noise in a context-sensitive manner in a network model. As a logical model, context-sensitive probabilistic Boolean networks (CSPBNs) account for molecular and genetic noise in the temporal context of gene functions. In a CSPBN with n genes and k contexts, however, a computational complexity of O(nk222n) (or O(nk2n)) is required for an accurate (or approximate) computation of the state transition matrix (STM) of the size (2n ? k) × (2n ? k) (or 2n × 2n). The evaluation of a steady state distribution (SSD) is more challenging. Recently, stochastic Boolean networks (SBNs) have been proposed as an efficient implementation of an instantaneous PBN.The notion of stochastic Boolean networks (SBNs) is extended for the general model of PBNs, i.e., CSPBNs. This yields a novel structure of context-sensitive SBNs (CSSBNs) for modeling the stochasticity in a GRN. A CSSBN enables an efficient simulation of a CSPBN with a complexity of O(nLk2n) for computing the state transition matrix, where L is a factor related to the required sequence length in CSSBN for achieving a desired accuracy. A time-frame expanded CSSBN can further efficiently simulate the stationary behavior of a CSPBN and allow for a tunable tradeoff between accuracy and efficiency. The CSSBN approach is more efficient than an analytical method and more accurate than an approximate analysis.Context-sensitive stochastic Boolean networks (CSSBNs) are proposed as an efficient approach to modeling the effects of gene perturbation and intervention in gene regulatory networks. A CSSBN analysis provides biologically meaningful insights into the oscillatory dynamics of the p53-Mdm2 network in a context-switching environment. It is shown that random gene perturbation has a greater effect on the final distribution of the steady state of a network compared to context switching activities. The CSSBN approach can further predict the steady state distribution of a glioma network under gene intervention. Ultimately, this will help drug discovery and develop effective drug intervention strategies.

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Computing smallest intervention strategies for multiple metabolic networks in a boolean model.

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Computing smallest intervention strategies for multiple metabolic networks in a boolean model.

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