Interactions of the S4 Helix of a Kv Channel with a Lipid Bilayer: Free Energy Calculations via Coarse-Grained Molecular Dynamics Simulations

Abstract

The S4 helix is a major element of the voltage-sensor of voltage-sensitive ion channels. This helix contains an array of positively charged sidechains and yet adopts a transmembrane orientation within the voltage sensor of a voltage-gated channel. Thus, from both mechanistic and a biosynthetic perspectives, the question of how the S4 helix may be stabilized in a membrane environment is of some importance. We have performed coarse-grained (CG) molecular dynamics (MD) simulations to calculate: (1) the free energy of insertion of a S4 helix; and (2) the free energy cost of driving a S4 helix through an angular motion in model membranes. Our results suggest that it is possibly to meta-stably insert a S4 helix in a TM orientation in a lipid bilayer. In this orientation, the helix is stabilized local bilayer deformation and by snorkelling of the sidechains of the positively-charged residues of S4 to interact with lipid phosphates and waters.