## CellNetAnalyzer

** Category** Cross-Omics>Pathway Analysis/Tools

** Abstract** CellNetAnalyzer (CNA) is a package for the MATLAB (see
Note 1) language and provides a comprehensive and user-friendly
environment for the structural and functional analysis of biochemical
and cellular networks.

CNA facilitates the analysis of metabolic (stoichiometric) as well as signaling and regulatory networks solely on their network topology, i.e. independently of kinetic mechanisms and parameters.

The core concept of visualization and interactivity is realized by interactive network maps where the abstract network model is linked with network graphics.

CNA provides an advanced collection of tools and algorithms for structural network analysis which can be started in a menu-controlled manner within the interactive network maps.

Recently, Application Programming Interface (API) functionalities have been added to enable interested users to call algorithms of CNA from external programs.

CellNetAnalyzer is the successor and further development of FluxAnalyzer 5.3. The latter was originally developed for structural analysis of mass-flow (metabolic) networks; CellNetAnalyzer extends FluxAnalyzer with a new framework for signal-flow (signaling and regulatory) networks.

CNA is a useful tool for systems biology, biotechnology, metabolic engineering, pharmacology, microbiology, molecular biology and chemical engineering.

CNA consists of (1) user-defined network projects and (2) a toolbox with numerous functions for structural network analysis:

1) Network projects - are created and designed by the user.

A network project can be “Mass-flow” type (modeling material flows as in metabolic or other stoichiometric reaction networks) or “Signal-flow” type (modeling information or signal flows as in signal transduction networks or regulatory networks).

Each network project contains an abstract (symbolic) network representation as well as one or several network graphics visualizing the network under investigation.

The abstract ‘network model’ is composed by declaring network elements such as reactions or compounds, whereas the network graphics have to be imported and thus created by other programs [e.g. CellDesigner (see G6G Abstract Number 20159), xfig, CorelDraw etc.; for signal-flow networks, ProMoT (see G6G Abstract Number 20332) provides an elegant solution to construct a network map and network model (in CellNetAnalyzer format) in one step].

Network model and graphical network representation can then be linked with the help of user interfaces (text boxes) leading to interactive network maps.

Interactive network maps are the central components of network projects.

The text boxes facilitate input and output (e.g. of reaction rates) directly within the network visualization.

2) The toolbox of CNA provides functions and procedures which, depending on the network type, facilitate stoichiometric (metabolic) network analysis or the analysis of signal-flow networks (see list below).

These functions can be started conveniently by a pull-down menu installed in the network maps and the user doesn't need to be aware of the mathematical details.

For speeding up extensive computations, a few algorithms use the MEX interface of MATLAB to call precompiled C files.

Computed results are displayed in the interactive maps, different coloration of the text boxes illustrate distinct contexts.

List of functions provided in CellNetAnalyzer --

Mass-flow (stoichiometric, metabolic) networks:

1) Metabolic flux analysis -

- a) classification of flux scenarios determinacy and redundancy) and rates (balance ability and calculability);
- b) calculation of flux distributions (for all types of flux scenarios);
- c) consistency checks in redundant systems;
- d) flux optimization subject to an arbitrary linear objective function (flux balance analysis, FBA);
- e) sensitivity analysis of calculated rates;
- f) feasibility check of a given scenario.

2) Analysis of basic topological / structural properties -

- a) graphical display of the stoichiometric matrix;
- b) computation of graph-theoretical path lengths in a directed and undirected graph representation of the reaction network, determination of network diameter;
- c) detection of (elementary) conservation relations, enzyme subsets, isozymes, blocked and parallel reactions;
- d) connectivity histogram.

3) Metabolic pathway analysis -

- a) large-scale calculation of elementary (flux) modes, extreme pathways and convex bases with new algorithms [optionally, METATOOL (Program for computing the null-space matrix, elementary modes and other structural properties of biochemical reaction networks) can be used (on the fly) for calculations];
- b) display of computed pathways in the flux maps;
- c) selection of pathways with respect to certain criteria;
- d) statistical analysis of pathways: 1) yield histogram, detection of optimal and suboptimal pathways; 2) reaction participation, prediction of mutant phenotypes; 3) quantitative estimating the importance of reactions: control-effective fluxes (CEF); 4) pathway lengths histogram; 5) export of computed elementary modes for external analysis.

4) Minimal cut sets -

- a) new (structural) approach for analyzing the fragility and for finding targets in biochemical reaction networks;
- b) efficient calculation of minimal cut sets [with respect to a user-defined set of (target) elementary modes];
- c) display of minimal cut sets within the network graphics; d) statistical evaluation and assessment of minimal cut sets.

5) Clipboard function; also enables arithmetic ('+','-','\','*') combination of different flux distributions for comparisons of different scenarios.

6) Comparing fluxes in a bar chart;

7) Network composer: editing the network structure (with the help of masks);

8) Saving and printing of network maps and/or the values of (computed or pre-defined) scenarios;

9) Systems Biology Markup Language (SBML) import and export, export of the stoichiometric matrix in ASCII format;

10) Zoom tool (for zooming in and out in large maps).

Signal flow (signaling, regulatory) networks:

1) Analysis of interaction graphs -

- a) basic topological properties;
- b) large-scale computation of all positive and negative signaling paths connecting inputs with outputs or of all signaling paths between a given pair of nodes, statistical analysis of these paths;
- c) large-scale computation of all positive and negative feedback loops, statistical analysis of these routes;
- d) computation of minimal cut sets (removing reactions or species) for a given set of paths or/and loops;
- e) computation of distance (shortest paths) matrices, separately for positive and negative paths;
- f) large-scale dependency analysis [which species has (positive/negative) influence on which species, identification of activators and inhibitors of a given species enabling predictions on perturbation experiments].

2) Analysis of logical (Boolean) interaction networks -

- a) arbitrary logical models (constructed with AND, OR and NOT operators) with multiple discrete levels can be set-up;
- b) logical steady state analysis for a given set of inputs / fixed states: useful for studying input-output behavior and signal processing;
- c) computation of (logical) minimal intervention sets (sets of knock- outs/knock-ins) repressing or provoking a certain behavior or function of the network;
- d) automated conversion of the logical model into an interaction graph;
- e) graphical display of the interaction matrix.

3) Clipboard function; also enables arithmetic combinations ('+','-','\','*') of different reaction or species (state) values for comparison of different scenarios;

4) Network composer: editing the network structure and properties of network elements;

5) Saving and printing of network maps and/or the values of (computed or pre-defined) scenarios;

6) Export of the network (interaction matrix);

7) Zoom tool (for zooming in and out in large maps).

*Note: MATLAB is a high-level language and interactive environment
that enables you to perform computationally intensive tasks faster than
with traditional programming languages such as C, C++, and FORTRAN.*

*System Requirements*

1) MATLAB version 6.1 or higher.

2) Some functions require the optimization toolbox of MATLAB (or/and GLPKMEX with the GLPK library).

GLPKMEX is a MATLAB MEX interface for the GLPK library developed by Nicolò Giorgetti.

GLPK (GNU Linear Programming Kit) is a set of routines written in the ANSI C programming language and organized in the form of a callable library.

It is intended for solving linear programming (LP), mixed integer programming (MIP), and other related problems.

*Manufacturer*

- Systems Biology group of
- Prof. Ernst Dieter Gilles
- Max Planck Institute for the Dynamics of Complex Technical Systems
- Magdeburg, Germany.

** Manufacturer Web Site**
CellNetAnalyzer

** Price** Academic use: free academic license. Commercial use:
licenses are distributed by
Max Planck Innovations GmbH.

** G6G Abstract Number** 20331

** G6G Manufacturer Number** 101743