Development of kinetic models in the nonlinear world of molecular cell biology

Increasingly, successful research on metabolic systems relies on teams of specialists. Because of the enormous complexity of these systems, many experimental groups have sought collaborations with theoreticians for data analysis and modeling. Predictably, cultural differences in scientific approach, methodology, assumptions, and language have led to some persistent difficulties in communication across the experiment-theory frontier. This report attempts to diagnose some of these difficulties from the perspective of 30 years' experience in both experimental and theoretical biology, and to suggest guidelines for effective collaboration between experimentalists and theorists. As these collaborations move to the level of cellular and molecular biology, effective communication will become all the more important because the simple linear rate laws of radiotracer and stable-isotope kinetics will no longer suffice. This is because every form of regulation and control, hallmarks of metabolic systems, results in nonlinear kinetics. To advance this transition to nonlinear cellular and molecular metabolic models and to facilitate communication between experimental and theoretical collaborators, a general procedure for incorporating control mechanisms in metabolic rate laws is developed based on the familiar rapid-equilibrium assumption of classical enzyme kinetics.