The Emerging Biophysics of Whole-Cell Biochemical Systems

The historical approach to unraveling biochemical function is to study isolated enzymes and/or complexes and to determine the kinetic mechanisms and associated parameter values for catalyzing certain reactions. While the reductionist approach has been fruitful, the buzzword of the present is 'integration'. Our current task is to assimilate and integrate the behavior of interacting systems of many enzymes and reactants. Understanding of such systems lays the foundation for modeling and simulation of whole-cell systems, a defining goal of the current era of biomedical science.

The constraints-based approach to modeling genome-scale biochemical systems has emerged as a useful tool for rational metabolic engineering. The power of constraints-based models lies in the fact that the constraints are based on physical laws, and thus contain no free parameters. I will show that the basic stoichiometric information, which is used to constrain biochemical fluxes in flux-balance analysis, provides information to constrain the fluxes according to the laws of thermodynamics. A rigorous thermodynamic basis for the study of biochemical reaction networks will be introduced. Characterization of living networks requires focusing new attention on a little-studied
subject in thermodynamics: the behavior of non-equilibrium steady-state systems (NESS). I will introduce the basic principles of NESS thermodynamics and discuss consequences for living systems.

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