Voltage Gated Cation Channels Activation: Towards an Ab-Initio Kinetic Model

Abstract

Many modulators, such as toxins, anesthetics or drugs, act on voltage-gated cation channels (VGCCs) by altering the kinetics of activation and/or deactivation of their voltage-sensing domains (VSD). So far, we have proposed a “static” model of the Kv1.2 VSD activation using brute force and modified molecular dynamics simulations and that agrees with a large body of experimental data. This model involves 5 states: α (activated), β, γ, δ (three intermediate) and e (resting) [Delemotte et al. 2011, Proc. Natl. Acad. Sci. USA, 108:6109-6114], and has enabled to gain access to the contribution of transmembrane voltage to the free energy of activation via calculation of the corresponding gating charge. Crucial details, however, are still missing, among which an estimation of the thermodynamic and kinetic stability of these states or of the minimum energy transition pathway linking them.In order to complete our understanding of VSD function, we produce the free energy landscape (FES) of the four transitions linking the Kv1.2 VSD conformations and estimate therefrom the corresponding the rate (kinetic) constants. This enables, not only to follow for the first time the pathway of activation of a VGCC VSD, but also to produce a complete ab-initio kinetic model of its activation based uniquely on parameters derived from an in-silico investigation. The G/V and Q/V curves (ionic current and gating current/voltage, respectively) characteristic of the function of wild type channels derived therefrom are then compared to electrophysiology recordings. The study is then extendable to investigate the modulation of VSD function by drugs, toxins, mutations or else lipid interaction.