Multiscale responsive kinetic modeling (MsRKM) of ion channels is powerful tool for coarse-graining ion transport into a series of intermediate states and transitions, creating a network description that links molecular level ion behavior to macroscopically observable ion flux. A central challenge in kinetic modeling is refining the potential solution space of parameters that fit a limited amount of experimental data to the correct solution for a given system. This work queries what information from electrophysiology assays and molecular modeling most efficiently refines kinetic solution space. Effective refinement requires narrowing the solution space based on known properties combined with sufficiently diverse data sets and effective optimization procedures. Using a leave-one-curve-out cross-validation technique on a range of current-conductance (I-V) and current-concentration (I-μ) relationships we find a subset of assays that are most influential. The solution space can be further refined by matching the dominant mechanistic cycles to the flux-limiting step, which can also be deduced from comparative I-V and I-μ curves. The results of this study reveal which electrophysiology assays most efficiently resolve kinetic solution space for ion channels, and how combining simulations, modeling and rational experimental design can lead to mechanistic insight into open channel currents.
Daum et al. (Sun,) studied this question.