Stiffness penalties for I_to,f optimized models across all optimization starts.

A) The normalized stiffness penalty seen as across all starts as a function of increasing free rate constants. B) The number of steps in an explicit ODE solver (MATLAB’s ODE45) when the penalties are not part of a model’s cost. Only two models may be successfully solved with the less computationally intensive explicit solvers, which indicates the model solutions are inherently stiff. C) When including a measure of model stiffness in the optimization routine [48], more models can successfully be solved in the ODE45 routine.

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