The circadian clock of Drosophila is a model pathway for research in biological clock mechanisms, both with traditional experimental approaches and with emerging systems biology approaches utilizing mathematical modeling and in silico computer simulation. Dynamic diurnal oscillations are achieved by the complex interaction of components as a system, and mathematical reconstruction has proven to be an invaluable means of understanding such systematic behavior. In this study, we implemented eight published models of the Drosophila circadian clock in Systems Biology Markup Language (SBML) for comparative systems biology studies using E-Cell Simulation Environment version 3, to examine the system-level requirements for the clock mechanism to be robust, by calculating the period and amplitude sensitivity coefficients with simulation experiments. While all models were generally robust as determined by the network topology of the oscillatory feedback loop structure, existing models place relatively strong emphasis on transcription regulation, although this is a limitation on robustness. We suggest that more comprehensive modeling including protein phosphorylation, polymerization, and nuclear transport with regard to amplitude sensitivity will be necessary for understanding the light entrainment and temperature compensation of circadian clocks.

Abstract Summary: A new version of the E-Cell simulation system, which runs on Windows as well as Linux, has been released as free software under the terms of the GNU General Public License. Availability: Downloadable from http://www.E-Cell.org

Article Free Access Share on The E-CELL project: towards integrative simulation of cellular processes Authors: Masaru Tomita Laboratory for Bioinformatics and Department of Environmental Informatics Laboratory for Bioinformatics and Department of Environmental InformaticsView Profile , Kenta Hashimoto Laboratory for Bioinformatics and School of Media and Governance Laboratory for Bioinformatics and School of Media and GovernanceView Profile , Koichi Takahashi Laboratory for Bioinformatics and School of Media and Governance Laboratory for Bioinformatics and School of Media and GovernanceView Profile , Yuri Matsuzaki Laboratory for Bioinformatics and School of Media and Governance Laboratory for Bioinformatics and School of Media and GovernanceView Profile , Ryo Matsushima Laboratory for Bioinformatics and School of Media and Governance Laboratory for Bioinformatics and School of Media and GovernanceView Profile , Katsuyuki Yugi Laboratory for Bioinformatics and School of Media and Governance Laboratory for Bioinformatics and School of Media and GovernanceView Profile , Fumihiko Miyoshi Laboratory for Bioinformatics and School of Media and Governance Laboratory for Bioinformatics and School of Media and GovernanceView Profile , Hisako Nakano Laboratory for Bioinformatics and Department of Policy Management, Keio University, 5322 Endo, Fujisawa, 252-8520 Japan Laboratory for Bioinformatics and Department of Policy Management, Keio University, 5322 Endo, Fujisawa, 252-8520 JapanView Profile , Yusuke Saito Laboratory for Bioinformatics and Department of Environmental Informatics Laboratory for Bioinformatics and Department of Environmental InformaticsView Profile , S. Shimizu Laboratory for Bioinformatics and Department of Zoology, Cambridge University, CB2 3EJ, UK Laboratory for Bioinformatics and Department of Zoology, Cambridge University, CB2 3EJ, UKView Profile , Yoichi Nakayama Laboratory for Bioinformatics and Department of Environmental Informatics Laboratory for Bioinformatics and Department of Environmental InformaticsView Profile Authors Info & Claims RECOMB '00: Proceedings of the fourth annual international conference on Computational molecular biologyApril 2000 Pages 290–298https://doi.org/10.1145/332306.332567Published:08 April 2000Publication History 1citation569DownloadsMetricsTotal Citations1Total Downloads569Last 12 Months13Last 6 weeks5 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my AlertsNew Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteeReaderPDF

MOTIVATION: Genome sequencing projects and further systematic functional analyses of complete gene sets are producing an unprecedented mass of molecular information for a wide range of model organisms. This provides us with a detailed account of the cell with which we may begin to build models for simulating intracellular molecular processes to predict the dynamic behavior of living cells. Previous work in biochemical and genetic simulation has isolated well-characterized pathways for detailed analysis, but methods for building integrative models of the cell that incorporate gene regulation, metabolism and signaling have not been established. We, therefore, were motivated to develop a software environment for building such integrative models based on gene sets, and running simulations to conduct experiments in silico. RESULTS: E-CELL, a modeling and simulation environment for biochemical and genetic processes, has been developed. The E-CELL system allows a user to define functions of proteins, protein-protein interactions, protein-DNA interactions, regulation of gene expression and other features of cellular metabolism, as a set of reaction rules. E-CELL simulates cell behavior by numerically integrating the differential equations described implicitly in these reaction rules. The user can observe, through a computer display, dynamic changes in concentrations of proteins, protein complexes and other chemical compounds in the cell. Using this software, we constructed a model of a hypothetical cell with only 127 genes sufficient for transcription, translation, energy production and phospholipid synthesis. Most of the genes are taken from Mycoplasma genitalium, the organism having the smallest known chromosome, whose complete 580 kb genome sequence was determined at TIGR in 1995. We discuss future applications of the E-CELL system with special respect to genome engineering. AVAILABILITY: The E-CELL software is available upon request. SUPPLEMENTARY INFORMATION: The complete list of rules of the developed cell model with kinetic parameters can be obtained via our web site at: http://e-cell.org/.