Deciphering the molecular mechanisms underlying open-channel ion conduction remains a formidable challenge—complicated by ensemble averaging in experiments and technical limitations in current simulations. In this talk, I will introduce a strategy to extract mechanistic insight directly from electrophysiological data using multiscale responsive kinetic modeling (MsRKM). This approach reveals consistent trends in current-voltage (IV), current-chemical potential (I-μ), and conductance profiles. I will demonstrate how these trends identify transition location of the flux-limiting step, uncover distinct origins of non-ohmic behavior for inward versus outward currents, and elucidate the mechanistic basis of open-channel rectification. Additionally, MsRKM identifies the concentration at which ion binding becomes flux-balanced with transfer or release. By integrating MsRKM with structural data on ion binding sites and electrophysiological profiles, we significantly constrain the kinetic solution space—enabling the resolution of both dominant and subdominant pathways of ion flux. This combined framework offers a complementary strategy for probing electrochemically driven transport—one that seeks to bridge the strengths of experimental and computational techniques in characterizing molecular transport mechanisms.
Jessica M. Swanson (Sun,) studied this question.