a linear framework for time-scale separation in nonlinear biochemical systems一个线性时间尺度分离非线性生化系统的框架.pdfVIP

A Linear Framework for Time-Scale Separation in Nonlinear Biochemical Systems Jeremy Gunawardena* Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, United States of America Abstract Cellular physiology is implemented by formidably complex biochemical systems with highly nonlinear dynamics, presenting a challenge for both experiment and theory. Time-scale separation has been one of the few theoretical methods for distilling general principles from such complexity. It has provided essential insights in areas such as enzyme kinetics, allosteric enzymes, G-protein coupled receptors, ion channels, gene regulation and post-translational modification. In each case, internal molecular complexity has been eliminated, leading to rational algebraic expressions among the remaining components. This has yielded familiar formulas such as those of Michaelis-Menten in enzyme kinetics, Monod-Wyman- Changeux in allostery and Ackers-Johnson-Shea in gene regulation. Here we show that these calculations are all instances of a single graph-theoretic framework. Despite the biochemical nonlinearity to which it is applied, this framework is entirely linear, yet requires no approximation. We show that elimination of internal complexity is feasible when the relevant graph is strongly connected. The framework provides a new methodology with the potential to subdue combinatorial explosion at the molecular level. Citation: Gunawardena J (2012) A Linear Framework for Time-Scale Separation in Nonlinear Biochemical Systems. PLoS ONE 7(5): e36321. doi:10.1371/ journal.pone.0036321 Editor: Kumar Selvarajoo, Keio University, Japan Received March 3, 2012; Accepted March 29, 2012; Published May 14, 2012 Copyright: 2012 Jeremy Gunawardena. This is an open-access article distributed under the terms of the Creative Commons Attri