Molecular Dynamic Studies of Transmembrane Voltage Sensor of NaChBac Channel in Up and Down State Models

Abstract

The voltage sensor domain (VSD) has been shown to behave as a functional independent module in a variety of voltage-activated ion channels and enzymes. VSD conformational transitions couple to the pore domain (PD) and bias the close-open conformational equilibrium in response to changes in membrane potential. A structural model of the Bacillus halodurans Na channel (NaChBac) voltage-sensor domain (VSD) in the activated or “up” state conformation has been derived from site-directed spin-labeling and EPR solvent accessibility data (Chakrapani et al., PNAS 107:5435, 2010). To examine a proposed VSD transition, the up conformation was further used to build a variety of putative “down” state models on the basis of a substitution of key salt-bridge pairs associated with S4 arginines and electrostatic couplings between E43 of S1 and R1 of S4 observed from electrophysiological data of NaChBac mutants (Paldi and Gurevitz, Biophysical J 99:456, 2010). 50-ns molecular dynamics simulations of the up and theoretical down conformations in lipid bilayer were performed to evaluate structure models and conformational dynamics of the transmembrane voltage sensor of NaChBac. The MD results illustrated structure stability of the transmembrane voltage sensing bundle with a possible conformation transition of an intracellular half of the S4 helix. From geometric analyses of MD data, the negative charge residues of S1 (E43), S2 (D60) and S3 (D93) share a role in the stability of S4 at the down configuration through salt-brdige neutralization of all four arginines.Acknowledgements: Ratchadaphiseksomphot Endowment, NRU(HR1155A) and Thai Government Stimulus Package 2.