Modelling in Molecular Biology
This volume consists of papers concerned with models and methods used in solving some fundamental problems of biosciences. They represent a wide spectrum of diverse ideas and trends. In particular, they reflect the genuinely interdisciplinary nature of re
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Bioengineering, University of Washington, Seattle, WA [email protected] Applied Mathematics and Bioengineering, University of Washington, Seattle [email protected] Bioengineering, University of Washington, Seattle, WA [email protected]
1 Introduction The traditional approach to unraveling functions of a biochemical system is to study isolated enzymes and/or complexes, and to determine their kinetic mechanisms for catalyzing given biochemical reactions along with estimates of the associated parameter values [41,47]. While this reductionist approach has been fruitful, the buzzwords of the present are integration and systems. One of the important tasks in current computational biology is to assimilate and integrate the behaviour of interacting systems of many enzymes and reactants. Understanding of such systems lays the foundation for modelling and simulation of whole-cell systems, a defining goal of the current era of biomedical science. In this chapter we discuss approaches to modelling biochemical systems, with an emphasis on the basic concepts and techniques used in building largescale integrated models of biochemical reaction networks. We consider the vices and virtues of the available methods; we speculate on what approaches are most reasonable for large-scale cellular modelling. How far current technology is from a reasonable quantification of wholecell biochemistry depends on what level of detail one considers. At the simplest level (considering only reaction stoichiometry), whole-genome metabolic models of several single-celled organisms have been developed [2,22,45,46,48]. At the more detailed level of kinetic modelling, models of the relatively simple metabolism of the red blood cell represent some of the most ambitious attempts to date at modelling whole-cell metabolism [23, 27, 28, 53]. While there is no one single approach to biochemical reaction network modelling deemed superior, all models have to satisfy a set of basic criteria. Recently, one of us has proposed the concept of “sustainable conservative cell” [5]. It is argued that all biochemical systems models need to properly
G. Ciobanu et al.(eds.), Modelling in Molecular Biology © Springer-Verlag Berlin Heidelberg 2004
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Daniel A. Beard, Hong Qian, and James B. Bassingthwaighte
represent the basic stoichiometry, with balanced chemical reactions, and the conservation of mass, energy, and charge. It is along this line that we carry on our discussion.
2 Stoichiometric Organization of Biochemical Systems We group approaches to modelling and simulation of biochemical systems into three hierarchical levels of detail: (1) stoichiometric, in which only the stoichiometry of the reaction network is known; (2) kinetic, in which detailed kinetic mechanisms and associated parameters are known for a reaction system; and (3) distributed, in which, along with detailed kinetics, information on the heterogeneous spatial organization of a biological system is considered. Stoichiometric rules are outlined in this section; kinetic
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