Molecular modeling and molecular dynamics simulation of voltage sensor domain of sodium channel in activated and resting states

Abstract

Voltage-gated sodium (Na[subscript v]) channels are membrane proteins that control the flux of sodium ions through membrane in both eukaryotic and prokaryotic cells. They are responsible for generation and propagation of electrical potential in excitable cells. A structure model of the voltage-sensor domain (VSD) of a Bacillus halodurans Na channel (NaChBac) in the activated or “Up” state was previously developed using Restrained Molecular Dynamics with experimental solvent accessibility data. In this study the putative resting or “Down” conformation was built based on biophysical and biochemical data. Structure and dynamics of both Up and Down conformations were investigated by MD simulations in phospholipid bilayer. From the MD results, the transmembrane structure of the Up state is more stable than that of the Down state. A counter charge exchange between the S4 arginines and the negatively charge residues in S1, S2 and S3 and the increase of water-filled crevice of the VSD cavity supported the observation from experimental studies. Although, all the interpretations of the study are relied on the model developed based on the crystal structure of K[subscript v] channels, the results of this study provide useful information for a general motion of the voltage sensing segment in a context of helical screw mechanism.