Multi-Dimensional Free Energy Landscape of Voltage Sensor Domain Activation

Abstract

Many modulators, such as toxins, anesthetics or drugs, act on voltage-gated channels by altering the activation and/or deactivation mechanism 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 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 multi-dimensional free energy landscape (FES) of the four transitions linking the Kv1.2 VSD conformations, enabling to follow for the first time the pathway of activation of a VSD. We then investigate how the free energy landscape of VSD activation is modified by a change in the lipid environment and by the mutation of key residues.