Estimating kinetic mechanisms with prior knowledge II: Behavioral constraints and numerical tests.

Kinetic mechanisms predict how ion channels and other proteins function at the molecular and cellular levels. Ideally, a kinetic model should explain new data but also be consistent with existing knowledge. In this two-part study, we present a mathematical and computational formalism that can be used to enforce prior knowledge into kinetic models using constraints. Here, we focus on constraints that quantify the behavior of the model under certain conditions, and on constraints that enforce arbitrary parameter relationships. The penalty-based optimization mechanism described here can be used to enforce virtually any model property or behavior, including those that cannot be easily expressed through mathematical relationships. Examples include maximum open probability, use-dependent availability, and nonlinear parameter relationships. We use a simple kinetic mechanism to test multiple sets of constraints that implement linear parameter relationships and arbitrary model properties and behaviors, and we provide numerical examples. This work complements and extends the companion article, where we show how to enforce explicit linear parameter relationships. By incorporating more knowledge into the parameter estimation procedure, it is possible to obtain more realistic and robust models with greater predictive power.