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1.  Qualitative translation of relations from BioPAX to SBML qual 
Bioinformatics  2012;28(20):2648-2653.
Motivation: The biological pathway exchange language (BioPAX) and the systems biology markup language (SBML) belong to the most popular modeling and data exchange languages in systems biology. The focus of SBML is quantitative modeling and dynamic simulation of models, whereas the BioPAX specification concentrates mainly on visualization and qualitative analysis of pathway maps. BioPAX describes reactions and relations. In contrast, SBML core exclusively describes quantitative processes such as reactions. With the SBML qualitative models extension (qual), it has recently also become possible to describe relations in SBML. Before the development of SBML qual, relations could not be properly translated into SBML. Until now, there exists no BioPAX to SBML converter that is fully capable of translating both reactions and relations.
Results: The entire nature pathway interaction database has been converted from BioPAX (Level 2 and Level 3) into SBML (Level 3 Version 1) including both reactions and relations by using the new qual extension package. Additionally, we present the new webtool BioPAX2SBML for further BioPAX to SBML conversions. Compared with previous conversion tools, BioPAX2SBML is more comprehensive, more robust and more exact.
Availability: BioPAX2SBML is freely available at and the complete collection of the PID models is available at
Supplementary Information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3467751  PMID: 22923304
2.  JSBML: a flexible Java library for working with SBML 
Bioinformatics  2011;27(15):2167-2168.
Summary: The specifications of the Systems Biology Markup Language (SBML) define standards for storing and exchanging computer models of biological processes in text files. In order to perform model simulations, graphical visualizations and other software manipulations, an in-memory representation of SBML is required. We developed JSBML for this purpose. In contrast to prior implementations of SBML APIs, JSBML has been designed from the ground up for the Java™ programming language, and can therefore be used on all platforms supported by a Java Runtime Environment. This offers important benefits for Java users, including the ability to distribute software as Java Web Start applications. JSBML supports all SBML Levels and Versions through Level 3 Version 1, and we have strived to maintain the highest possible degree of compatibility with the popular library libSBML. JSBML also supports modules that can facilitate the development of plugins for end user applications, as well as ease migration from a libSBML-based backend.
Availability: Source code, binaries and documentation for JSBML can be freely obtained under the terms of the LGPL 2.1 from the website
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3137227  PMID: 21697129
3.  LibSBMLSim: a reference implementation of fully functional SBML simulator 
Bioinformatics  2013;29(11):1474-1476.
Motivation: The Systems Biology Markup Language (SBML) is currently supported by >230 software tools, among which 160 support numerical integration of ordinary differential equation (ODE) models. Although SBML is a widely accepted standard within this field, there is still no language-neutral library that supports all features of SBML for simulating ODE models. Therefore, a demand exists for a simple portable implementation of a numerical integrator that supports SBML to enhance the development of a computational platform for systems biology.
Results: We implemented a library called libSBMLSim, which supports all the features of SBML and confirmed that the library passes all tests in the SBML test suite including those for SBML Events, AlgebraicRules, ‘fast’ attribute on Reactions and Delay. LibSBMLSim is implemented in the C programming language and does not depend on any third-party library except libSBML, which is a library to handle SBML documents. For the numerical integrator, both explicit and implicit methods are written from scratch to support all the functionality of SBML features in a straightforward implementation. We succeeded in implementing libSBMLSim as a platform-independent library that can run on most common operating systems (Windows, MacOSX and Linux) and also provides several language bindings (Java, C#, Python and Ruby).
Availability: The source code of libSBMLSim is available from LibSBMLSim is distributed under the terms of LGPL.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC3661052  PMID: 23564843
4.  libAnnotationSBML: a library for exploiting SBML annotations 
Bioinformatics  2009;25(17):2292-2293.
Summary: The Systems Biology Markup Language (SBML) is an established community XML format for the markup of biochemical models. With the introduction of SBML level 2 version 3, specific model entities, such as species or reactions, can now be annotated using ontological terms. These annotations, which are encoded using the resource description framework (RDF), provide the facility to specify definite terms to individual components, allowing software to unambiguously identify such components and thus link the models to existing data resources.
libSBML is an application programming interface library for the manipulation of SBML files. While libSBML provides the facilities for reading and writing such annotations from and to models, it is beyond the scope of libSBML to provide interpretation of these terms. The libAnnotationSBML library introduced here acts as a layer on top of libSBML linking SBML annotations to the web services that describe these ontological terms. Two applications that use this library are described: SbmlSynonymExtractor finds name synonyms of SBML model entities and SbmlReactionBalancer checks SBML files to determine whether specifed reactions are elementally balanced.
PMCID: PMC2734318  PMID: 19561017
5.  LibSBML: An API Library for SBML 
Bioinformatics (Oxford, England)  2008;24(6):880-881.
LibSBML is an application programming interface library for reading, writing, manipulating and validating content expressed in the Systems Biology Markup Language (SBML) format. It is written in ISO C and C++, provides language bindings for Common Lisp, Java, Python, Perl, MATLAB and Octave, and includes many features that facilitate adoption and use of both SBML and the library. Developers can embed libSBML in their applications, saving themselves the work of implementing their own SBML parsing, manipulation, and validation software.
LibSBML 3 was released in August 2007. Source code, binaries and documentation are freely available under LGPL open-source terms from
PMCID: PMC2517632  PMID: 18252737
6.  A two-way interface between limited Systems Biology Markup Language and R 
BMC Bioinformatics  2004;5:190.
Systems Biology Markup Language (SBML) is gaining broad usage as a standard for representing dynamical systems as data structures. The open source statistical programming environment R is widely used by biostatisticians involved in microarray analyses. An interface between SBML and R does not exist, though one might be useful to R users interested in SBML, and SBML users interested in R.
A model structure that parallels SBML to a limited degree is defined in R. An interface between this structure and SBML is provided through two function definitions: write.SBML() which maps this R model structure to SBML level 2, and read.SBML() which maps a limited range of SBML level 2 files back to R. A published model of purine metabolism is provided in this SBML-like format and used to test the interface. The model reproduces published time course responses before and after its mapping through SBML.
List infrastructure preexisting in R makes it well-suited for manipulating SBML models. Further developments of this SBML-R interface seem to be warranted.
PMCID: PMC539231  PMID: 15585059
7.  SBMLeditor: effective creation of models in the Systems Biology Markup Language (SBML) 
BMC Bioinformatics  2007;8:79.
The need to build a tool to facilitate the quick creation and editing of models encoded in the Systems Biology Markup language (SBML) has been growing with the number of users and the increased complexity of the language. SBMLeditor tries to answer this need by providing a very simple, low level editor of SBML files. Users can create and remove all the necessary bits and pieces of SBML in a controlled way, that maintains the validity of the final SBML file.
SBMLeditor is written in JAVA using JCompneur, a library providing interfaces to easily display an XML document as a tree. This decreases dramatically the development time for a new XML editor. The possibility to include custom dialogs for different tags allows a lot of freedom for the editing and validation of the document. In addition to Xerces, SBMLeditor uses libSBML to check the validity and consistency of SBML files. A graphical equation editor allows an easy manipulation of MathML. SBMLeditor can be used as a module of the Systems Biology Workbench.
SBMLeditor contains many improvements compared to a generic XML editor, and allow users to create an SBML model quickly and without syntactic errors.
PMCID: PMC1831489  PMID: 17341299
8.  SBML2TikZ: supporting the SBML render extension in LaTeX 
Bioinformatics  2010;26(21):2794-2795.
Motivation: The SBML Render Extension enables coloring and shape information of biochemical models to be stored in the Systems Biology Markup Language (SBML). Rendering of this stored graphical information in a portable and well supported system such as TeX would be useful for researchers preparing documentation and presentations. In addition, since the Render Extension is not yet supported by many applications, it is helpful for such rendering functionality be extended to the more popular CellDesigner annotation as well.
Results: SBML2TikZ supports automatic generation of graphics for biochemical models in the popular TeX typesetting system. The library generates a script of TeX macro commands for the vector graphics languages PGF/TikZ that can be compiled into scalable vector graphics described in a model.
Availability: Source code, documentation and compiled binaries for the SBML2TikZ library can be found at In addition, a web application is available at
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2981496  PMID: 20829443
9.  SBML2LaTEX: Conversion of SBML files into human-readable reports 
Bioinformatics  2009;25(11):1455-1456.
Summary: The XML-based Systems Biology Markup Language (SBML) has emerged as a standard for storage, communication and interchange of models in systems biology. As a machine-readable format XML is difficult for humans to read and understand. Many tools are available that visualize the reaction pathways stored in SBML files, but many components, e.g. unit declarations, complex kinetic equations or links to MIRIAM resources, are often not made visible in these diagrams. For a broader understanding of the models, support in scientific writing and error detection, a human-readable report of the complete model is needed. We present SBML2LaTEX, a Java-based stand-alone program to fill this gap. A convenient web service allows users to directly convert SBML to various formats, including DVI, LaTEX and PDF, and provides many settings for customization.
Availability: Source code, documentation and a web service are freely available at
Supplementary information:Supplementary data are available at Bioinformatics online.
PMCID: PMC2682517  PMID: 19307240
10.  SBML-SAT: a systems biology markup language (SBML) based sensitivity analysis tool 
BMC Bioinformatics  2008;9:342.
It has long been recognized that sensitivity analysis plays a key role in modeling and analyzing cellular and biochemical processes. Systems biology markup language (SBML) has become a well-known platform for coding and sharing mathematical models of such processes. However, current SBML compatible software tools are limited in their ability to perform global sensitivity analyses of these models.
This work introduces a freely downloadable, software package, SBML-SAT, which implements algorithms for simulation, steady state analysis, robustness analysis and local and global sensitivity analysis for SBML models. This software tool extends current capabilities through its execution of global sensitivity analyses using multi-parametric sensitivity analysis, partial rank correlation coefficient, SOBOL's method, and weighted average of local sensitivity analyses in addition to its ability to handle systems with discontinuous events and intuitive graphical user interface.
SBML-SAT provides the community of systems biologists a new tool for the analysis of their SBML models of biochemical and cellular processes.
PMCID: PMC2529325  PMID: 18706080
11.  JSim, an open-source modeling system for data analysis 
F1000Research  2013;2:288.
JSim is a simulation system for developing models, designing experiments, and evaluating hypotheses on physiological and pharmacological systems through the testing of model solutions against data. It is designed for interactive, iterative manipulation of the model code, handling of multiple data sets and parameter sets, and for making comparisons among different models running simultaneously or separately. Interactive use is supported by a large collection of graphical user interfaces for model writing and compilation diagnostics, defining input functions, model runs, selection of algorithms solving ordinary and partial differential equations, run-time multidimensional graphics, parameter optimization (8 methods), sensitivity analysis, and Monte Carlo simulation for defining confidence ranges. JSim uses Mathematical Modeling Language (MML) a declarative syntax specifying algebraic and differential equations. Imperative constructs written in other languages (MATLAB, FORTRAN, C++, etc.) are accessed through procedure calls. MML syntax is simple, basically defining the parameters and variables, then writing the equations in a straightforward, easily read and understood mathematical form. This makes JSim good for teaching modeling as well as for model analysis for research.   For high throughput applications, JSim can be run as a batch job.  JSim can automatically translate models from the repositories for Systems Biology Markup Language (SBML) and CellML models. Stochastic modeling is supported. MML supports assigning physical units to constants and variables and automates checking dimensional balance as the first step in verification testing. Automatic unit scaling follows, e.g. seconds to minutes, if needed. The JSim Project File sets a standard for reproducible modeling analysis: it includes in one file everything for analyzing a set of experiments: the data, the models, the data fitting, and evaluation of parameter confidence ranges. JSim is open source; it and about 400 human readable open source physiological/biophysical models are available at
PMCID: PMC3901508  PMID: 24555116
12.  Version 6 of the consensus yeast metabolic network refines biochemical coverage and improves model performance 
Updates to maintain a state-of-the art reconstruction of the yeast metabolic network are essential to reflect our understanding of yeast metabolism and functional organization, to eliminate any inaccuracies identified in earlier iterations, to improve predictive accuracy and to continue to expand into novel subsystems to extend the comprehensiveness of the model. Here, we present version 6 of the consensus yeast metabolic network (Yeast 6) as an update to the community effort to computationally reconstruct the genome-scale metabolic network of Saccharomyces cerevisiae S288c. Yeast 6 comprises 1458 metabolites participating in 1888 reactions, which are annotated with 900 yeast genes encoding the catalyzing enzymes. Compared with Yeast 5, Yeast 6 demonstrates improved sensitivity, specificity and positive and negative predictive values for predicting gene essentiality in glucose-limited aerobic conditions when analyzed with flux balance analysis. Additionally, Yeast 6 improves the accuracy of predicting the likelihood that a mutation will cause auxotrophy. The network reconstruction is available as a Systems Biology Markup Language (SBML) file enriched with Minimium Information Requested in the Annotation of Biochemical Models (MIRIAM)-compliant annotations. Small- and macromolecules in the network are referenced to authoritative databases such as Uniprot or ChEBI. Molecules and reactions are also annotated with appropriate publications that contain supporting evidence. Yeast 6 is freely available at as three separate SBML files: a model using the SBML level 3 Flux Balance Constraint package, a model compatible with the MATLAB® COBRA Toolbox for backward compatibility and a reconstruction containing only reactions for which there is experimental evidence (without the non-biological reactions necessary for simulating growth).
Database URL:
PMCID: PMC3739857  PMID: 23935056
13.  Antimony: a modular model definition language 
Bioinformatics  2009;25(18):2452-2454.
Motivation: Model exchange in systems and synthetic biology has been standardized for computers with the Systems Biology Markup Language (SBML) and CellML, but specialized software is needed for the generation of models in these formats. Text-based model definition languages allow researchers to create models simply, and then export them to a common exchange format. Modular languages allow researchers to create and combine complex models more easily. We saw a use for a modular text-based language, together with a translation library to allow other programs to read the models as well.
Summary: The Antimony language provides a way for a researcher to use simple text statements to create, import, and combine biological models, allowing complex models to be built from simpler models, and provides a special syntax for the creation of modular genetic networks. The libAntimony library allows other software packages to import these models and convert them either to SBML or their own internal format.
Availability: The Antimony language specification and the libAntimony library are available under a BSD license from
PMCID: PMC2735663  PMID: 19578039
14.  The systems biology simulation core algorithm 
BMC Systems Biology  2013;7:55.
With the increasing availability of high dimensional time course data for metabolites, genes, and fluxes, the mathematical description of dynamical systems has become an essential aspect of research in systems biology. Models are often encoded in formats such as SBML, whose structure is very complex and difficult to evaluate due to many special cases.
This article describes an efficient algorithm to solve SBML models that are interpreted in terms of ordinary differential equations. We begin our consideration with a formal representation of the mathematical form of the models and explain all parts of the algorithm in detail, including several preprocessing steps. We provide a flexible reference implementation as part of the Systems Biology Simulation Core Library, a community-driven project providing a large collection of numerical solvers and a sophisticated interface hierarchy for the definition of custom differential equation systems. To demonstrate the capabilities of the new algorithm, it has been tested with the entire SBML Test Suite and all models of BioModels Database.
The formal description of the mathematics behind the SBML format facilitates the implementation of the algorithm within specifically tailored programs. The reference implementation can be used as a simulation backend for Java™-based programs. Source code, binaries, and documentation can be freely obtained under the terms of the LGPL version 3 from Feature requests, bug reports, contributions, or any further discussion can be directed to the mailing list
PMCID: PMC3707837  PMID: 23826941
Systems biology; Biological networks; Mathematical modeling; Simulation; Algorithms; Ordinary differential equation systems; Numerical integration; Software engineering
15.  SBMLsqueezer: A CellDesigner plug-in to generate kinetic rate equations for biochemical networks 
BMC Systems Biology  2008;2:39.
The development of complex biochemical models has been facilitated through the standardization of machine-readable representations like SBML (Systems Biology Markup Language). This effort is accompanied by the ongoing development of the human-readable diagrammatic representation SBGN (Systems Biology Graphical Notation). The graphical SBML editor CellDesigner allows direct translation of SBGN into SBML, and vice versa. For the assignment of kinetic rate laws, however, this process is not straightforward, as it often requires manual assembly and specific knowledge of kinetic equations.
SBMLsqueezer facilitates exactly this modeling step via automated equation generation, overcoming the highly error-prone and cumbersome process of manually assigning kinetic equations. For each reaction the kinetic equation is derived from the stoichiometry, the participating species (e.g., proteins, mRNA or simple molecules) as well as the regulatory relations (activation, inhibition or other modulations) of the SBGN diagram. Such information allows distinctions between, for example, translation, phosphorylation or state transitions. The types of kinetics considered are numerous, for instance generalized mass-action, Hill, convenience and several Michaelis-Menten-based kinetics, each including activation and inhibition. These kinetics allow SBMLsqueezer to cover metabolic, gene regulatory, signal transduction and mixed networks. Whenever multiple kinetics are applicable to one reaction, parameter settings allow for user-defined specifications. After invoking SBMLsqueezer, the kinetic formulas are generated and assigned to the model, which can then be simulated in CellDesigner or with external ODE solvers. Furthermore, the equations can be exported to SBML, LaTeX or plain text format.
SBMLsqueezer considers the annotation of all participating reactants, products and regulators when generating rate laws for reactions. Thus, for each reaction, only applicable kinetic formulas are considered. This modeling scheme creates kinetics in accordance with the diagrammatic representation. In contrast most previously published tools have relied on the stoichiometry and generic modulators of a reaction, thus ignoring and potentially conflicting with the information expressed through the process diagram. Additional material and the source code can be found at the project homepage (URL found in the Availability and requirements section).
PMCID: PMC2412839  PMID: 18447902
16.  Annotation of SBML models through rule-based semantic integration 
Journal of Biomedical Semantics  2010;1(Suppl 1):S3.
The creation of accurate quantitative Systems Biology Markup Language (SBML) models is a time-intensive, manual process often complicated by the many data sources and formats required to annotate even a small and well-scoped model. Ideally, the retrieval and integration of biological knowledge for model annotation should be performed quickly, precisely, and with a minimum of manual effort.
Here we present rule-based mediation, a method of semantic data integration applied to systems biology model annotation. The heterogeneous data sources are first syntactically converted into ontologies, which are then aligned to a small domain ontology by applying a rule base. We demonstrate proof-of-principle of this application of rule-based mediation using off-the-shelf semantic web technology through two use cases for SBML model annotation. Existing tools and technology provide a framework around which the system is built, reducing development time and increasing usability.
Integrating resources in this way accommodates multiple formats with different semantics, and provides richly-modelled biological knowledge suitable for annotation of SBML models. This initial work establishes the feasibility of rule-based mediation as part of an automated SBML model annotation system.
Detailed information on the project files as well as further information on and comparisons with similar projects is available from the project page at
PMCID: PMC2903722  PMID: 20626923
17.  SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools 
BMC Systems Biology  2013;7:135.
Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing.
We present the Systems Biology Markup Language (SBML) Qualitative Models Package (“qual”), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models.
SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks.
PMCID: PMC3892043  PMID: 24321545
18.  Multistate Model Builder (MSMB): a flexible editor for compact biochemical models 
BMC Systems Biology  2014;8:42.
Building models of molecular regulatory networks is challenging not just because of the intrinsic difficulty of describing complex biological processes. Writing a model is a creative effort that calls for more flexibility and interactive support than offered by many of today’s biochemical model editors. Our model editor MSMB — Multistate Model Builder — supports multistate models created using different modeling styles.
MSMB provides two separate advances on existing network model editors. (1) A simple but powerful syntax is used to describe multistate species. This reduces the number of reactions needed to represent certain molecular systems, thereby reducing the complexity of model creation. (2) Extensive feedback is given during all stages of the model creation process on the existing state of the model. Users may activate error notifications of varying stringency on the fly, and use these messages as a guide toward a consistent, syntactically correct model. MSMB default values and behavior during model manipulation (e.g., when renaming or deleting an element) can be adapted to suit the modeler, thus supporting creativity rather than interfering with it. MSMB’s internal model representation allows saving a model with errors and inconsistencies (e.g., an undefined function argument; a syntactically malformed reaction). A consistent model can be exported to SBML or COPASI formats. We show the effectiveness of MSMB’s multistate syntax through models of the cell cycle and mRNA transcription.
Using multistate reactions reduces the number of reactions need to encode many biochemical network models. This reduces the cognitive load for a given model, thereby making it easier for modelers to build more complex models. The many interactive editing support features provided by MSMB make it easier for modelers to create syntactically valid models, thus speeding model creation. Complete information and the installation package can be found at MSMB is based on Java and the COPASI API.
PMCID: PMC4234935  PMID: 24708852
Systems biology; Biological networks; Mathematical modeling; Chemical reaction systems; COPASI; SBML; Software; Model editor; Multistate
19.  Using chemical organization theory for model checking 
Bioinformatics  2009;25(15):1915-1922.
Motivation: The increasing number and complexity of biomodels makes automatic procedures for checking the models' properties and quality necessary. Approaches like elementary mode analysis, flux balance analysis, deficiency analysis and chemical organization theory (OT) require only the stoichiometric structure of the reaction network for derivation of valuable information. In formalisms like Systems Biology Markup Language (SBML), however, information about the stoichiometric coefficients required for an analysis of chemical organizations can be hidden in kinetic laws.
Results: First, we introduce an algorithm that uncovers stoichiometric information that might be hidden in the kinetic laws of a reaction network. This allows us to apply OT to SBML models using modifiers. Second, using the new algorithm, we performed a large-scale analysis of the 185 models contained in the manually curated BioModels Database. We found that for 41 models (22%) the set of organizations changes when modifiers are considered correctly. We discuss one of these models in detail (BIOMD149, a combined model of the ERK- and Wnt-signaling pathways), whose set of organizations drastically changes when modifiers are considered. Third, we found inconsistencies in 5 models (3%) and identified their characteristics. Compared with flux-based methods, OT is able to identify those species and reactions more accurately [in 26 cases (14%)] that can be present in a long-term simulation of the model. We conclude that our approach is a valuable tool that helps to improve the consistency of biomodels and their repositories.
Availability: All data and a JAVA applet to check SBML-models is available from
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2712341  PMID: 19468053
20.  Precise generation of systems biology models from KEGG pathways 
BMC Systems Biology  2013;7:15.
The KEGG PATHWAY database provides a plethora of pathways for a diversity of organisms. All pathway components are directly linked to other KEGG databases, such as KEGG COMPOUND or KEGG REACTION. Therefore, the pathways can be extended with an enormous amount of information and provide a foundation for initial structural modeling approaches. As a drawback, KGML-formatted KEGG pathways are primarily designed for visualization purposes and often omit important details for the sake of a clear arrangement of its entries. Thus, a direct conversion into systems biology models would produce incomplete and erroneous models.
Here, we present a precise method for processing and converting KEGG pathways into initial metabolic and signaling models encoded in the standardized community pathway formats SBML (Levels 2 and 3) and BioPAX (Levels 2 and 3). This method involves correcting invalid or incomplete KGML content, creating complete and valid stoichiometric reactions, translating relations to signaling models and augmenting the pathway content with various information, such as cross-references to Entrez Gene, OMIM, UniProt ChEBI, and many more.
Finally, we compare several existing conversion tools for KEGG pathways and show that the conversion from KEGG to BioPAX does not involve a loss of information, whilst lossless translations to SBML can only be performed using SBML Level 3, including its recently proposed qualitative models and groups extension packages.
Building correct BioPAX and SBML signaling models from the KEGG database is a unique characteristic of the proposed method. Further, there is no other approach that is able to appropriately construct metabolic models from KEGG pathways, including correct reactions with stoichiometry. The resulting initial models, which contain valid and comprehensive SBML or BioPAX code and a multitude of cross-references, lay the foundation to facilitate further modeling steps.
PMCID: PMC3623889  PMID: 23433509
KEGG; KGML; SBML; BioPAX; Modeling; Systems biology; Qualitative modeling; Quantitative modeling; Converter; Comparison
21.  KEGGconverter: a tool for the in-silico modelling of metabolic networks of the KEGG Pathways database 
BMC Bioinformatics  2009;10:324.
The KEGG Pathway database is a valuable collection of metabolic pathway maps. Nevertheless, the production of simulation capable metabolic networks from KEGG Pathway data is a challenging complicated work, regardless the already developed tools for this scope. Originally used for illustration purposes, KEGG Pathways through KGML (KEGG Markup Language) files, can provide complete reaction sets and introduce species versioning, which offers advantages for the scope of cellular metabolism simulation modelling. In this project, KEGGconverter is described, implemented also as a web-based application, which uses as source KGML files, in order to construct integrated pathway SBML models fully functional for simulation purposes.
A case study of the integration of six human metabolic pathways from KEGG depicts the ability of KEGGconverter to automatically produce merged and converted to SBML fully functional pathway models, enhanced with default kinetics. The suitability of the developed tool is demonstrated through a comparison with other state-of-the art relevant software tools for the same data fusion and conversion tasks, thus illustrating the problems and the relevant workflows. Moreover, KEGGconverter permits the inclusion of additional reactions in the resulting model which represent flux cross-talk with neighbouring pathways, providing in this way improved simulative accuracy. These additional reactions are introduced by exploiting relevant semantic information for the elements of the KEGG Pathways database. The architecture and functionalities of the web-based application are presented.
KEGGconverter is capable of producing integrated analogues of metabolic pathways appropriate for simulation tasks, by inputting only KGML files. The web application acts as a user friendly shell which transparently enables the automated biochemically correct pathway merging, conversion to SBML format, proper renaming of the species, and insertion of default kinetic properties for the pertaining reactions. The tool is available at:
PMCID: PMC2764712  PMID: 19814801
22.  Biographer: web-based editing and rendering of SBGN compliant biochemical networks 
Bioinformatics  2013;29(11):1467-1468.
Motivation: The rapid accumulation of knowledge in the field of Systems Biology during the past years requires advanced, but simple-to-use, methods for the visualization of information in a structured and easily comprehensible manner.
Results: We have developed biographer, a web-based renderer and editor for reaction networks, which can be integrated as a library into tools dealing with network-related information. Our software enables visualizations based on the emerging standard Systems Biology Graphical Notation. It is able to import networks encoded in various formats such as SBML, SBGN-ML and jSBGN, a custom lightweight exchange format. The core package is implemented in HTML5, CSS and JavaScript and can be used within any kind of web-based project. It features interactive graph-editing tools and automatic graph layout algorithms. In addition, we provide a standalone graph editor and a web server, which contains enhanced features like web services for the import and export of models and visualizations in different formats.
Availability: The biographer tool can be used at and downloaded from the web page The different software packages, including a server-indepenent version as well as a web server for Windows and Linux based systems, are available at under the open-source license LGPL.
Contact: or
PMCID: PMC3661053  PMID: 23574737
23.  The Input Signal Step Function (ISSF), a Standard Method to Encode Input Signals in SBML Models with Software Support, Applied to Circadian Clock Models 
Journal of Biological Rhythms  2012;27(4):328-332.
Time-dependent light input is an important feature of computational models of the circadian clock. However, publicly available models encoded in standard representations such as the Systems Biology Markup Language (SBML) either do not encode this input or use different mechanisms to do so, which hinders reproducibility of published results as well as model reuse. The authors describe here a numerically continuous function suitable for use in SBML for models of circadian rhythms forced by periodic light-dark cycles. The Input Signal Step Function (ISSF) is broadly applicable to encoding experimental manipulations, such as drug treatments, temperature changes, or inducible transgene expression, which may be transient, periodic, or mixed. It is highly configurable and is able to reproduce a wide range of waveforms. The authors have implemented this function in SBML and demonstrated its ability to modify the behavior of publicly available models to accurately reproduce published results. The implementation of ISSF allows standard simulation software to reproduce specialized circadian protocols, such as the phase-response curve. To facilitate the reuse of this function in public models, the authors have developed software to configure its behavior without any specialist knowledge of SBML. A community-standard approach to represent the inputs that entrain circadian clock models could particularly facilitate research in chronobiology.
PMCID: PMC3423168  PMID: 22855577
drug treatments; circadian rhythms; systems biology; BioModels SED-ML SBO
24.  MicrobesFlux: a web platform for drafting metabolic models from the KEGG database 
BMC Systems Biology  2012;6:94.
Concurrent with the efforts currently underway in mapping microbial genomes using high-throughput sequencing methods, systems biologists are building metabolic models to characterize and predict cell metabolisms. One of the key steps in building a metabolic model is using multiple databases to collect and assemble essential information about genome-annotations and the architecture of the metabolic network for a specific organism. To speed up metabolic model development for a large number of microorganisms, we need a user-friendly platform to construct metabolic networks and to perform constraint-based flux balance analysis based on genome databases and experimental results.
We have developed a semi-automatic, web-based platform (MicrobesFlux) for generating and reconstructing metabolic models for annotated microorganisms. MicrobesFlux is able to automatically download the metabolic network (including enzymatic reactions and metabolites) of ~1,200 species from the KEGG database (Kyoto Encyclopedia of Genes and Genomes) and then convert it to a metabolic model draft. The platform also provides diverse customized tools, such as gene knockouts and the introduction of heterologous pathways, for users to reconstruct the model network. The reconstructed metabolic network can be formulated to a constraint-based flux model to predict and analyze the carbon fluxes in microbial metabolisms. The simulation results can be exported in the SBML format (The Systems Biology Markup Language). Furthermore, we also demonstrated the platform functionalities by developing an FBA model (including 229 reactions) for a recent annotated bioethanol producer, Thermoanaerobacter sp. strain X514, to predict its biomass growth and ethanol production.
MicrobesFlux is an installation-free and open-source platform that enables biologists without prior programming knowledge to develop metabolic models for annotated microorganisms in the KEGG database. Our system facilitates users to reconstruct metabolic networks of organisms based on experimental information. Through human-computer interaction, MicrobesFlux provides users with reasonable predictions of microbial metabolism via flux balance analysis. This prototype platform can be a springboard for advanced and broad-scope modeling of complex biological systems by integrating other “omics” data or 13 C- metabolic flux analysis results. MicrobesFlux is available at and will be continuously improved based on feedback from users.
PMCID: PMC3447728  PMID: 22857267
25.  MEMOSys 2.0: an update of the bioinformatics database for genome-scale models and genomic data 
The MEtabolic MOdel research and development System (MEMOSys) is a versatile database for the management, storage and development of genome-scale models (GEMs). Since its initial release, the database has undergone major improvements, and the new version introduces several new features. First, the novel concept of derived models allows users to create model hierarchies that automatically propagate modifications along their order. Second, all stored components can now be easily enhanced with additional annotations that can be directly extracted from a supplied Systems Biology Markup Language (SBML) file. Third, the web application has been substantially revised and now features new query mechanisms, an easy search system for reactions and new link-out services to publicly available databases. Fourth, the updated database now contains 20 publicly available models, which can be easily exported into standardized formats for further analysis. Fifth, MEMOSys 2.0 is now also available as a fully configured virtual image and can be found online at and
Database URL:
PMCID: PMC3924767  PMID: 24532766

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