Ion channels, transporters, and redox-active membrane enzymes operate in dynamic environments shaped by fluctuating electrochemical gradients, which drive the movement of charged substrates across biological membranes. Despite great progress, uncovering the molecular mechanisms of transport—especially under nonequilibrium conditions—remains an outstanding challenge.

In this seminar, I will introduce Multiscale Responsive Kinetic Modeling (MsRKM), a framework that integrates simulations and experiment to extract transport mechanisms consistent with molecular-level insights and macroscopic observations. By incorporating electrochemically responsive rate constants, MsRKM allows direct comparison with current-voltage (I–V) profiles and predicts how mechanisms shift under varying conditions.

Our findings show that chemical and electrical gradients—even when equal in Nernstian magnitude—drive fundamentally different transport behaviors. For example, ClC-ec1 exhibits gradient-dependent mechanisms while the Shaker K⁺ channel requires gradient-shifting off-pathway flux. MsRKM also disentangles the physical origins of voltage- and concentration-dependent current profiles (I–V vs. I–μ) and explains directional flux (rectification) by linking ion binding site locations to voltage sensitivity.

In an era of rapid advances in computational and experimental techniques, this work highlights the power of integrating simulation, experiment, and mechanistic modeling to uncover molecular mechanisms—providing new insight into how life operates under nonequilibrium conditions.