Stiffness penalties for I_Na optimized models across all optimization starts.

A) The normalized stiffness penalty seen as across all starts as a function of increasing free rate constants. There is decline in the minimum stiffness penalty from four to six free rate constants followed by a plateau in the minimum penalty for topologies with greater than six free rate constants B) The number of steps in an explicit ODE solver (MATLAB’s ODE45) when the penalties are not part of model cost. Few 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, more models can successfully be solved in the ODE45 routine.

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