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Spatial Rule-Based Modeling: A Method and Its Application to the Human Mitotic Kinetochore
Bio Systems Analysis Group, Institute of Computer Science, Jena Centre for Bioinformatics and Friedrich Schiller University Jena, Ernst-Abbe-Platz 2, D-0007743 Jena, Germany
German Cancer Research Centre, DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 29 March 2013; in revised form: 5 June 2013 / Accepted: 25 June 2013 / Published: 2 July 2013
Abstract: A common problem in the analysis of biological systems is the combinatorial explosion that emerges from the complexity of multi-protein assemblies. Conventional formalisms, like differential equations, Boolean networks and Bayesian networks, are unsuitable for dealing with the combinatorial explosion, because they are designed for a restricted state space with fixed dimensionality. To overcome this problem, the rule-based modeling language, BioNetGen, and the spatial extension, SRSim, have been developed. Here, we describe how to apply rule-based modeling to integrate experimental data from different sources into a single spatial simulation model and how to analyze the output of that model. The starting point for this approach can be a combination of molecular interaction data, reaction network data, proximities, binding and diffusion kinetics and molecular geometries at different levels of detail. We describe the technique and then use it to construct a model of the human mitotic inner and outer kinetochore, including the spindle assembly checkpoint signaling pathway. This allows us to demonstrate the utility of the procedure, show how a novel perspective for understanding such complex systems becomes accessible and elaborate on challenges that arise in the formulation, simulation and analysis of spatial rule-based models.
Keywords: keyword; rule-based; modeling; simulation; 3D space; SRSim software; kinetochore structure; spindle assembly checkpoint; mitosis; structural analysis
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Ibrahim, B.; Henze, R.; Gruenert, G.; Egbert, M.; Huwald, J.; Dittrich, P. Spatial Rule-Based Modeling: A Method and Its Application to the Human Mitotic Kinetochore. Cells 2013, 2, 506-544.
Ibrahim B, Henze R, Gruenert G, Egbert M, Huwald J, Dittrich P. Spatial Rule-Based Modeling: A Method and Its Application to the Human Mitotic Kinetochore. Cells. 2013; 2(3):506-544.
Ibrahim, Bashar; Henze, Richard; Gruenert, Gerd; Egbert, Matthew; Huwald, Jan; Dittrich, Peter. 2013. "Spatial Rule-Based Modeling: A Method and Its Application to the Human Mitotic Kinetochore." Cells 2, no. 3: 506-544.