The Karyote physico-chemical genomic, proteomic, metabolic cell modeling system.

Modeling approaches to the dynamics of a living cell are presented that are strongly based on its underlying physical and chemical processes and its hierarchical spatio-temporal organization. Through the inclusion of a broad spectrum of processes and a rigorous analysis of the multiple scale nature of cellular dynamics, we are attempting to advance cell modeling and its applications. The presentation focuses on our cell modeling system, which integrates data archiving and quantitative physico-chemical modeling and information theory to provide a seamless approach to the modeling/data analysis endeavor. Thereby the rapidly growing mess of genomic, proteomic, metabolic, and cell physiological data can be automatically used to develop and calibrate a predictive cell model. The discussion focuses on the Karyote cell modeling system and an introduction to the CellX and VirusX models. The Karyote software system integrates three elements: (1) a model-building and data archiving module that allows one to define a cell type to be modeled through its reaction network, structure, and transport processes as well as to choose the surrounding medium and other parameters of the phenomenon to be modeled; (2) a genomic, proteomic, metabolic cell simulator that solves the equations of metabolic reaction, transcription/translation polymerization and the exchange of molecules between parts of the cell and with the surrounding medium; and (3) an information theory module (ITM) that automates model calibration and development, and integrates a variety of data types with the cell dynamic computations. In Karyote, reactions may be fast (equilibrated) or slow (finite rate), and the special effects of enzymes and other minority species yielding steady-state cycles of arbitrary complexities are accounted for. These features of the dynamics are handled via rigorous multiple scale analysis. A user interface allows for an automated generation and solution of the equations of multiple timescale, compartmented dynamics. Karyote is based on a fixed intracellular structure. However, cell response to changes in the host medium, damage, development or transformation to abnormality can involve dramatic changes in intracellular structure. As this changes the nature of the cellular dynamics, a new model, CellX, is being developed based on the spatial distribution of concentration and other variables. This allows CellX to capture the self-organizing character of cellular behavior. The self-assembly of organelles, viruses, and other subcellular bodies is being addressed in a second new model, VirusX, that integrates molecular mechanics and continuum theory. VirusX is designed to study the influence of a host medium on viral self-assembly, structural stability, infection of a single cell, and transmission of disease.

Toward Automated Cell Model Development through Information Theory†.

The objective of this paper is to present a methodology for developing and calibrating models of complex reaction/transport systems. In particular, the complex network of biochemical reaction/transport processes and their spatial organization make the development of a predictive model of a living cell a grand challenge for the 21st century. However, advances in reaction/transport modeling and the exponentially growing databases of genomic, proteomic, metabolic, and bioelectric data make cell modeling feasible, if these two elements can be automatically integrated in an unbiased fashion. In this paper, we present a procedure to integrate data with a new cell model, Karyote, that accounts for many of the physical processes needed to attain the goal of predictive modeling. Our integration methodology is based on the use of information theory. The model is integrated with a variety of types and qualities of experimental data using an objective error assessment approach. Data that can be used in this approach include NMR, spectroscopy, microscopy, and electric potentiometry. The approach is demonstrated on the well-studied Trypanosoma brucei system. A major obstacle for the development of a predictive cell model is that the complexity of these systems makes it unlikely that any model presently available will soon be complete in terms of the set of processes accounted for. Thus, one is faced with the challenge of calibrating and running an incomplete model. We present a probability functional method that allows the integration of experimental data and soft information such as choice of error measure, a priori information, and physically motivated regularization to address the incompleteness challenge.