Coupling of Channel Fluctuations in Ion Permeation and Selectivity in Bacterial Sodium Channel NavAb

Abstract

Even though crystallographic structures of several cation channels are known at atomistic resolution, the molecular basis for selective ion permeation, and in particular, the role of structural fluctuations of the channel in that process, remains unclear. The determination of structures of voltage-gated sodium channels opens the way to elucidating the mechanism of sodium permeation and selectivity. Recent molecular simulation studies of bacterial sodium channel NavAb (Chakrabarti et al., PNAS 110, 11331-11336, 2013) suggest that Na+ binding and permeation through the selectivity filter are coupled to the conformational isomerization of Glu177 side chains from an outfacing conformation to a lumen-facing conformation, resulting in a high rate of Na+ diffusion through the selectivity filter.To clarify the role of channel dynamics on ion permeation and selectivity, we examine the effect of structural constraints systematically. Specifically, we characterize the mechanism of cation permeation in the absence of conformational “dunking” of Glu177 side chains. In addition, we investigate the effect of structural restraints imposed on the pore helices to prevent channel closure, as well as of applied voltage, on channel fluctuations and transport properties. Results of simulations totaling over 100 microseconds indicate that restricting Glu177 conformations, either directly or through global structural restraints on the helices of the pore domain, modulates cation binding and permeation. Further, applying strong external voltage gradients significantly displaces the conformational equilibrium of the Glu177 side chains, thereby also modulating the mechanism of ion permeation in NavAb.