Computational electrophysiology of potassium and chloride channels

Ion channels have been traditionally studied by either structural biology or electrophysiology techniques. While both approaches are extremely powerful, a direct comparison of the “structural world” with the “functional” one is not always straightforward, due to resolution and time scales differences between these techniques. Here, I will present how Molecular Dynamics (MD) based simulations under applied voltage can be used as a bridging “Computational Electrophysiology” (CompEl) approach, to study ion permeation and gating at the atomistic scale, simultaneously enabling direct comparison with experimentally measured single channel currents. Progress in the force field development allowed us to record, for the first
time, full I-V curves for several potassium channels, revealing the mechanism of inward rectification. We show how ion permeation in these channels, occurring via “full” direct knock-on mechanism, underlies their high permeation rates. Selectivity filter gating and its modulation by small molecules in the TREK-1 channel will be discussed as well. Finally, our work on the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) shows a bifurcated permeation pathway, with a hitherto unknown regulation mechanism.