PT  - JOURNAL ARTICLE
AU  - Lucie Delemotte
AU  - Marina A. Kasimova
AU  - Daniel Sigg
AU  - Michael L. Klein
AU  - Vincenzo Carnevale
AU  - Mounir Tarek
TI  - Exploring the Complex Dynamics of an Ion Channel Voltage Sensor Domain via Computation
AID  - 10.1101/108217
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 108217
4099  - http://biorxiv.org/content/early/2017/02/16/108217.short
4100  - http://biorxiv.org/content/early/2017/02/16/108217.full
AB  - Voltage-gated ion channels are ubiquitous proteins that orchestrate electrical signaling across excitable membranes. Key to their function is activation of the voltage sensor domain (VSD), a transmembrane four alpha-helix bundle that triggers channel opening. Modeling of currents from electrophysiology experiments yields a set of kinetic parameters for a given channel, but no direct molecular insight. Here we use molecular dynamics (MD) simulations to determine the free energy landscape of VSD activation and to, ultimately, predict the time evolution of the resulting gating currents. Our study provides the long-sought-for bridge between electrophysiology and microscopic molecular dynamics and confirms, as already suggested on the basis of experiments, that rate-limiting barriers play a critical role in activation kinetics.