1. Modular Approach To Modeling Of The Apoptosis Machinery E. O. Kutumova 1,2,*, R. N. Sharipov 1,3,2, F. A. Kolpakov 1,2 1 Institute of Systems Biology, Novosibirsk, Russia; 2 Design Technological Institute of Digital Techniques SB RAS, Novosibirsk, Russia; 3 Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia; *Contacts: e.o.kutumova@gmail.com Motivation Apoptosis is a highly regulated and evolutionary conserved pathway of cell death that plays a critical role in development and maintenance of tissue homeostasis. Formal description of pro- and anti-apoptotic machinery has been enriched significantly in recent years, and a range of mathematical models has been created. But mainly they describe different segments of implicated pathways, and the total model of apoptosis regulation has not been developed yet. Goals Development of the comprehensive map of pro- and anti- apoptotic pathways for in silico experiments based on the existing mathematical models and information from databases on biological pathways. Dividing a model into modules to simplify its analysis and processing. Multi-experiment parameters fitting of the separated modules. Simulation and analysis of the whole model. Methods The BioUML platform was used for the composite model (fig. 1) and individual modules (fig. 2) creation. All modules were presented in the SBML format with the SBGN notation. Existing mathematical models were found in the literature and Biomodels database. Reactom and Transpath databases were used as a source of additional reactions. BioUML optimization plug-in was developed for the model parameters estimation. Results Integrated model of apoptosis includes: 13 functional modules: modules resulting activation of caspase-8 by the death stimuli (TRAIL, CD95L, TNF-a); modules concern of the survival stimuli (p53, EGF, NF-kB); Mitochondrion level; modules related to the activation of caspase-3 under the influence of cytochrome C and SMAC; direct activation of executioner caspases by caspase-8 (type I cells) and caspase-12; PARP-1 and apoptosis execution phase modules. 5 different compartments: Nucleus, Cytoplasm, Mitochondria, Extracellular space and Endosomal volume. 286 species: proteins and their complexes; proteins modifications such as different form of the same molecule (e.g. caspases and procaspases); proteins transformations (e.g. phosphorylation). 684 reactions including 607 parameters: Mass action kinetics; Michaelis-Menten kinetics. Acknowledgments Part of this work was partially supported by European Committee grants №037590 “Net2Drug” and №202272 “LipidomicNet”. References 1.M. Bentele, et al. The Journal of Cell Biology, 2004, 166(6):839-851. 2.L. Neumann, et al. Molecular Systems Biology, 2010, 6(352). 3.C. Scaffidi, et al. The EMBO Journal, 1998, 17(6):1675–1687. 4.Hua F, et al. The Journal of Immunology, 2005, 175:985-995. Figure 1. The integrated apoptosis model overview Figure 2. CD95 module constructed based on the model of M. Bentele et al. [1] and results of its fitting to experimental datasets [1-4] simultaneously. Bentele M et al., 2004 Neumann L et al., 2010 Scaffidi C et al., 1998 Hua F et al., 2005