Dräger Andreas, Hassis Nadine, Supper Jochen, Schröder Adrian, Zell Andreas
Center for Bioinformatics Tübingen (ZBIT), University of Tübingen, Sand 1, 72076 Tübingen, Germany.
BMC Syst Biol. 2008 Apr 30;2:39. doi: 10.1186/1752-0509-2-39.
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).
诸如SBML（系统生物学标记语言）之类的机器可读表示形式的标准化推动了复杂生化模型的发展。这项工作伴随着人类可读的图形表示形式SBGN（系统生物学图形符号）的不断发展。图形化的SBML编辑器CellDesigner允许将SBGN直接转换为SBML，反之亦然。然而，对于动力学速率定律的赋值，这个过程并不简单，因为它通常需要手动组装以及动力学方程的特定知识。
SBMLsqueezer通过自动生成方程促进了这一建模步骤，克服了手动分配动力学方程时极易出错且繁琐的过程。对于每个反应，动力学方程是从化学计量学、参与的物种（例如蛋白质、mRNA或简单分子）以及SBGN图的调控关系（激活、抑制或其他调节）推导出来的。这些信息允许区分例如翻译、磷酸化或状态转换。所考虑的动力学类型众多，例如广义质量作用、希尔、便利型以及几种基于米氏方程的动力学，每种都包括激活和抑制。这些动力学使SBMLsqueezer能够涵盖代谢、基因调控、信号转导和混合网络。当多种动力学适用于一个反应时，参数设置允许用户进行自定义规范。调用SBMLsqueezer后，动力学公式会生成并分配给模型，然后可以在CellDesigner中或使用外部常微分方程求解器进行模拟。此外，这些方程可以导出为SBML、LaTeX或纯文本格式。
SBMLsqueezer在为反应生成速率定律时会考虑所有参与反应物、产物和调节剂的注释。因此，对于每个反应，只考虑适用的动力学公式。这种建模方案根据图形表示创建动力学。相比之下，大多数先前发布的工具依赖于反应的化学计量学和通用调节剂，从而忽略了通过过程图表达的信息并可能与之冲突。补充材料和源代码可在项目主页上找到（在“可用性和要求”部分中找到URL）。
