SBMLsqueezer: a CellDesigner plug-in to generate kinetic rate equations for biochemical networks

Abstract

Background: 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.

Results: 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.

Conclusion: 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).

Figure 1

The SBMLsqueezer work flow. This graphic depicts the progression through SBMLsqueezer. The first step is to construct or open a diagrammatic model in CellDesigner. Then SBMLsqueezer can be started through the plug-in menu (step 1). The first window shows the standard kinetics and enables the user to specify the type of kinetics to be applied whenever there are multiple choices. By clicking on &ldquoGenerate&rdquo (step 2), the kinetics are compiled and presented. If necessary, warnings are indicated along with the respective formula. The kinetic equations summarized in the table can be altered by double-clicking on the name of the equation, which is taken from the SBO. SBMLsqueezer then offers a list of all applicable kinetic equations for the given reaction. Subsequently, all kinetics can be assigned to the SBML model and exported to plain text or LaTeX.

Figure 2

Modeling reactions one by one using the context menu. SBMLsqueezer provides a context menu which enables the user to create kinetic equations for the model one by one. Therefore, SBMLsqueezer analyzes the structure of the reaction and offers a selection of possible rate laws for the desired reaction. The names shown in this dialog window are generic terms. The tool tips associated with each option present the detailed SBO term for the particular choice. An equation preview [34] facilitates selection of an appropriate rate equation. Furthermore, SBMLsqueezer provides a radio button to set the reaction as reversible or irreversible possibly changing the selection of available rate laws.