Schwacke John H, Voit Eberhard O
Department of Biostatistics, Bioinformatics, and Epidemiology, Medical University of South Carolina, 135 Cannon Street, Suite 303, Charleston, SC 29425, USA.
J Theor Biol. 2005 Sep 7;236(1):21-38. doi: 10.1016/j.jtbi.2005.02.013. Epub 2005 Apr 2.
Understanding biochemical system dynamics is becoming increasingly important for insights into the functioning of organisms and for biotechnological manipulations, and additional techniques and methods are needed to facilitate investigations of dynamical properties of systems. Extensions to the method of Ingalls and Sauro, addressing time-dependent sensitivity analysis, provide a new tool for executing such investigations. We present here the results of sample analyses using time-dependent sensitivities for three model systems taken from the literature, namely an anaerobic fermentation pathway in yeast, a negative feedback oscillator modeling cell-cycle phenomena, and the Mitogen Activated Protein (MAP) kinase cascade. The power of time-dependent sensitivities is particularly evident in the case of the MAPK cascade. In this example it is possible to identify the emergence of a concentration of MAPKK that provides the best response with respect to rapid and efficient activation of the cascade, while over- and under-expression of MAPKK relative to this concentration have qualitatively different effects on the transient response of the cascade. Also of interest is the quite general observation that phase-plane representations of sensitivities in oscillating systems provide insights into the manner with which perturbations in the envelope of the oscillation result from small changes in initial concentrations of components of the oscillator. In addition to these applied analyses, we present an algorithm for the efficient computation of time-dependent sensitivities for Generalized Mass Action (GMA) systems, the most general of the canonical system representations of Biochemical Systems Theory (BST). The algorithm is shown to be comparable to, or better than, other methods of solution, as exemplified with three biochemical systems taken from the literature.
理解生化系统动力学对于洞察生物体的功能以及生物技术操作变得越来越重要，并且需要额外的技术和方法来促进对系统动力学特性的研究。对英格尔斯和绍罗方法的扩展，涉及时间依赖性敏感性分析，为开展此类研究提供了一种新工具。我们在此展示了对取自文献的三个模型系统使用时间依赖性敏感性进行样本分析的结果，即酵母中的厌氧发酵途径、模拟细胞周期现象的负反馈振荡器以及丝裂原活化蛋白（MAP）激酶级联反应。时间依赖性敏感性的强大之处在MAPK级联反应的案例中尤为明显。在这个例子中，可以确定一个MAPKK浓度的出现，它对于级联反应的快速有效激活提供了最佳响应，而相对于该浓度，MAPKK的过表达和低表达对级联反应的瞬态响应具有质的不同影响。同样有趣的是一个相当普遍的观察结果，即振荡系统中敏感性的相平面表示能够深入了解振荡器组件初始浓度的微小变化如何导致振荡包络中的扰动。除了这些应用分析，我们还提出了一种用于高效计算广义质量作用（GMA）系统时间依赖性敏感性的算法，GMA系统是生化系统理论（BST）中最通用的规范系统表示形式。正如从文献中选取的三个生化系统所例证的那样，该算法被证明与其他求解方法相当或更优。
