Structural and dynamical properties of voltage sensor domain of activated and resting potassium channel in lipid bilayer by molecular dynamics simulation

Abstract

Voltage-gated ion channels sense changes in transmembrane electric fields by the rearrangement of the positively charged residues, predominantly arginines, along the S4 helix in the voltage-sensing domain (VSD). The key significance for the S4 motion is to drive the gate located in the pore domain of the channels opening or closing in respond to changes in the membrane potential. The molecular mechanism of voltage-dependent conformational transition of VSD is not clearly understood. Unfortunately, crystal structures of a number of voltage-gated ion channels including Kv1.2, KvAP, NavAb and NavRh, could represent the voltage sensor in an only one state so-called “Up” or activated conformation. In this thesis, a computational study of the activated (Up) and resting (Down) conformations of the isolated VSD from the prokaryotic K+ channel KvAP is presented. The Down sensor model was developed based on the PaDSAR approach, molecular dynamics simulations and solvent continuum gating charge calculations. The results show that KvAP-VSD transforms from the resting to activated conformations by an upward tilt and slide of the S4 helix to the upper face of membrane bilayer with a distance of 3-5Å. This motion was associated with the movement of gating charge arginines and a change in salt-bridge arginines, giving rise to an increase of water penetration into the voltage sensor core. The reorientation of helical dipoles on S4 and a change in the internal dielectric constant of VSD should involve with the voltage-sensing mechanism. Comparison of the simulations with and without external electric fields revealed that the presence of membrane potential helps to stabilize the Down conformation of KvAP-VSD. The gating charge for the models was calculated to be 2.82±0.09e per monomer. This is in good agreement with the experimental estimates of 12–14e measured for the Shaker K+ tetrameric channel.