Ion Transport from Physics to Physiology: the Missing Rungs in the Ladder
Exploring the Complex Dynamics of an Ion Channel Voltage Sensor Domain via ComputationMounir Tarek
Coauthor(s) : Lucie Delemotte, Marina A. Kasimova, Daniel Sigg, Michael L. Klein, Vincenzo Carnevale and Mounir Tarek
Voltage sensors (VSDs) are ubiquitous domains of voltage-gated ion channels that act as transducers of transmembrane electric signals within and across excitable cells. As such they are implicated in key physiological processes e.g. cellular contraction, cardiac and neuronal electrical activity. Among the body of discoveries that have contributed to increase our knowledge of VSDs function was the recording of transient currents of very low amplitude called today gating currents. These currents initially measured in the 1970s follow from the reorganization of charged residues of the protein in response to a change in the transmembrane voltage. Interpreting gating currents in light of simplified kinetic models has been for decades, and remains to this day, the main approach to investigate the molecular determinants of VSD activation in order to better understand voltage-gated ion channel function, as well as dysfunction that might result for instance from genetic mutations.
Here, we developed and alternative strategy in which we extracted from molecular models of the VSDs of the Kv1.2 Potassium voltage gate channel, the potential of mean force (PMF) that describes the energetics of their activation mechanism. We then deduce gating currents that are directly comparable to experimental recordings, showing how the MD based kinetic models of VSD activation represents an innovative tool to answer questions regarding voltage-gated channel function. Our calculation of the voltage sensor PMF represents therefore a crucial milestone toward a quantitative, molecular-level picture of an ion channel gating.