# SBMLSimulator: A Java Tool for Model Simulation and Parameter Estimation in Systems Biology

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## Abstract

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## 1. Introduction

^{TM}framework EvA2 [12] has been shown to be promising for the optimization of biological systems [11,13,14,15,16].

## 2. Implementation

## 3. Results and Discussion

#### 3.1. Graphical User Interface

**Figure 1.**The graphical user interface (GUI) of The Systems Biology Markup Language (SBML)simulator. The figure shows the main window of SBMLsimulator after importing the model by Bucher et al. [28]. SBMLsimulator enables the user to modify initial quantities (middle left part of window) and to choose the quantities for plotting (upper left). Furthermore, at the bottom of the window the user can specify settings for simulation, such as the integration routine, the simulation start and end time, the simulation step size, and the quality function for comparing the simulated data to experimental data. The simulation can be started by clicking on the simulation button. The right part shows an intermediate solution, whereby the original values are depicted by shapes and the simulated values dependent on the current set of parameters are shown as curves. In the given state, the parameter optimization already found a set of parameters that fit the predefined values with a small error.

#### 3.2. Parameter Estimation Study

**Figure 2.**Distribution of parameters estimated with SBMLsimulator. One hundred parameter estimations with SBMLsimulator for the model by Bucher et al. [28] were run on a computer cluster. The distribution of the 50 estimations with the best fitness values is shown here. For each parameter the estimated values were divided by the original parameter value prior to plotting. It is obvious from the plot that all parameters were estimated closely around their original values. The figure has been created with R software package [40].

**Table 1.**Estimated parameters with units, their initial intervals and their intervals throughout parameter estimation for the model by Bucher et al. [28].

Parameter | Unit | Minimum Initial Value | Maximum Initial Value | Minimum Value | Maximum Value |
---|---|---|---|---|---|

Import_ASLpOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Import_ASLoOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Import_ASpOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Export_ASLpOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Export_ASLoOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Export_ASoOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Export_AS_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Export_ASL_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Import_AS_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Import_ASoOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Export_ASpOH_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

k_PON_OH_c | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

k_PON_ASL_c | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 0.1 | ${10}^{-6}$ | 0.1 |

Import_ASL_k | $\text{mL}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 1 | ${10}^{-6}$ | 1 |

fu_AS | dimensionless | ${10}^{-6}$ | 1 | ${10}^{-6}$ | 1 |

fu_ASL | dimensionless | ${10}^{-6}$ | 1 | ${10}^{-6}$ | 1 |

CYP3A4_ASoOH_Vmax | $\text{pmol}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 100 | ${10}^{-6}$ | 100 |

CYP3A4_ASLpOH_Vmax | $\text{pmol}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 100 | ${10}^{-6}$ | 100 |

CYP3A4_ASLoOH_Vmax | $\text{pmol}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 100 | ${10}^{-6}$ | 100 |

CYP3A4_ASpOH_Vmax | $\text{pmol}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 100 | ${10}^{-6}$ | 100 |

UGT1A3_AS_Vmax | $\text{pmol}\xb7{\text{min}}^{-1}$ | ${10}^{-6}$ | 100 | ${10}^{-6}$ | 100 |

## 4. Conclusions

## 5. Availability and Requirements

^{TM}archive file (JAR) together with a documentation of the program.

**Project name:**SBMLsimulator

**Project homepage:**http://www.cogsys.cs.uni-tuebingen.de/software/SBMLsimulator/

**Contact:**[email protected]

**Operating systems:**Platform independent, i.e., for all systems for which a Java

^{TM}Virtual Machine (JVM) is available.

**Programming language:**Java

^{TM}

**Other requirements:**Java

^{TM}Runtime Environment (JRE) 1.6 or above

**License:**GNU Lesser General Public License (LGPL) version 3

## Acknowledgments

## Author Contributions

## Abbreviations/Nomenclature

AMIGO | Advanced Model Identification in systems biology using Global Optimization |

COPASI | COmplex PAthway SImulator |

CellML | Cell Markup Language |

GUI | graphical user interface |

JAR | Java ^{TM} archive file |

JRE | Java ^{TM} Runtime Environment |

JSBML | Java ^{TM} SBML |

JVM | Java ^{TM} Virtual Machine |

LGPL | GNU Lesser General Public License |

ODE | ordinary differential equation |

SBML | Systems Biology Markup Language |

SBML-PET | SBML Parameter Estimation Tool |

SBSCL | Systems Biology Simulation Core Library |

XML | Extensible Markup Language |

## Conflicts of Interest

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**MDPI and ACS Style**

Dörr, A.; Keller, R.; Zell, A.; Dräger, A.
SBMLSimulator: A Java Tool for Model Simulation and Parameter Estimation in Systems Biology. *Computation* **2014**, *2*, 246-257.
https://doi.org/10.3390/computation2040246

**AMA Style**

Dörr A, Keller R, Zell A, Dräger A.
SBMLSimulator: A Java Tool for Model Simulation and Parameter Estimation in Systems Biology. *Computation*. 2014; 2(4):246-257.
https://doi.org/10.3390/computation2040246

**Chicago/Turabian Style**

Dörr, Alexander, Roland Keller, Andreas Zell, and Andreas Dräger.
2014. "SBMLSimulator: A Java Tool for Model Simulation and Parameter Estimation in Systems Biology" *Computation* 2, no. 4: 246-257.
https://doi.org/10.3390/computation2040246