Molecular Dynamics Studies of Ion Conduction in a Prokaryotic Channel

Abstract

Recently, the crystal structures of putative bacterial, voltage-gated sodium channels have been published, giving an atomic scale view of the NaChBac family of voltage-gated sodium channels. The selectivity filters of the open pore structure of NavMs (McCusker et al (2012) Nature Comm. 3, 1102) and the closed pore structure of NavAb (Payandeh et al (2011) Nature 475, 353) differ only on the order of 1-2 A in diameter. Previously published studies aimed at predicting the mechanism of ion selectivity through free energy surfaces have not provided a consistent free energy surface. Electrophysiology studies suggest that sodium selectivity in the NaChBac family is slight when compared to the potassium selectivity in potassium-selective ion channels (Shaya et al (2011) PNAS 108, 12313). Multi-microsecond equilibrium simulations of NavAb by Chakrabarti et al. suggest that conformational movements of the glutamate side chains are correlated to sodium movement through the selectivity filter (PNAS (2013) 110, 11331).We present microsecond timescale molecular dynamics simulations of ion conduction through a truncated model of the NavAb pore as a function of applied voltage, in solutions containing sodium, potassium, and both, and as a function of concentration. The model NavAb is constructed from the NavAb pore in which the S5 and S6 helices are truncated, creating an open pore, and embedded in a neon support. The S5 and S6 helices and the support are restrained, but the pore helices and selectivity filter are unrestrained. We show that conformational distribution of the glutamate side chains is voltage dependent. The dependence of selectivity on voltage, concentration, and cations present is demonstrated. Additionally, it is apparent that the rate of and predominant mechanism of conduction is not only dependent upon the voltage and cation but also upon the direction of current.