Kenta Hashimoto

E-CELL: software environment for whole-cell simulation.

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/.

Computational challenges in cell simulation: a software engineering approach

Molecular biologys advent in the 20th century has exponentially increased our knowledge about the inner workings of life. We have dozens of completed genomes and an array of high-throughput methods to characterize gene encodings and gene product operation. The question now is how we will assemble the various pieces. In other words, given sufficient information about a living cells molecular components, can we predict its behavior? We introduce the major classes of cellular processes relevant to modeling, discuss software engineerings role in cell simulation, and identify cell simulation requirements. Our E-Cell project aims to develop the theories, techniques, and software platforms necessary for whole-cell-scale modeling, simulation, and analysis. Since the projects launch in 1996, we have built a variety of cell models, and we are currently developing new models that vary with respect to species, target subsystem, and overall scale.

The E-CELL project: Towards integrative simulation of cellular processes

The E-CELL project was launched in 1996 at Keio University in order to model and simulate various cellular processes with the ultimate goal of simulating the cell as a whole. The first version of the E-CELL simulation system, which is a generic software package for cell modeling, was completed in 1997. The E-CELL system enables us to model not only metabolic pathways but also other higher-order cellular processes such as protein synthesis and membrane transport within the same framework. These various processes can then be integrated into a single simulation model.Using the E-CELL system, we have successfully constructed a virtual cell with 127 genes sufficient for “self-support”. The gene set was selected from the genome of Mycoplasma genitalium the organism having the smallest known genome. The set includes genes for transcription, translation, the glycolysis pathway for energy production, membrane transport, and the phospholipid biosynthesis pathway for membrane structure.The E-CELL system has been made available for beta testing from our website (http: //www.e-cell.org).

Integrative modeling of gene expression and metabolism with E-CELL System

A gene-expression model for an E-CELL simulation was constructed, and the simulation was carried out. The model was integrated with a metabolism model of the self-sustaining virtual cell model which was constructed based on aMycoplasma genitalium cell. Details of the model structure and the results of the simulation are shown. AnEscherichia coli lac-operon model was also constructed by integrating and abstracting the gene-expression model. Wherever possible, experimental parameters were used to construct the model

The E-CELL project: towards integrative simulation of cellular processes

The E-CELL project was launched in 1996 at Keio University in order to model and simulate various cellular processes with the ultimate goal of simulating the cell as a whole. The first version of the E-CELL simulation system, which is a generic software package for cell modeling, was completed in 1997. The E-CELL system enables us to model not only metabolic pathways but also other higher-order cellular processes such as protein synthesis and membrane transport within the same framework. These various processes can then be integrated into a single simulation model.