Physical understanding of complex multiscale biochemical models via algorithmic simplification: Glycolysis in Saccharomyces cerevisiae

Large-scale models of cellular reaction networks are usually highly complex and characterized by a wide spectrum of time scales, making a direct interpretation and understanding of the relevant mechanisms almost impossible. We address this issue by demonstrating the benefits provided by model reduction techniques. We employ the Computational Singular Perturbation (CSP) algorithm to analyze the glycolytic pathway of intact yeast cells in the oscillatory regime. As a primary object of research for many decades, glycolytic oscillations represent a paradigmatic candidate for studying biochemical function and mechanisms. Using a previously published full-scale model of glycolysis, we show that, due to fast dissipative time scales, the solution is asymptotically attracted on a low dimensional manifold. Without any further input from the investigator, CSP clarifies several long-standing questions in the analysis of glycolytic oscillations, such as the origin of the oscillations in the upper part of glycolysis, the importance of energy and redox status, as well as the fact that neither the oscillations nor cell–cell synchronization can be understood in terms of glycolysis as a simple linear chain of sequentially coupled reactions.