Bases of Sodium Channel Selectivity Among Organic Cations

Abstract

Hille's (1971) seminal study of the organic cation selectivity of voltage-gated sodium channels, showed a striking, sharp size cut-off for ion permeation. No ion species with an aliphatic moiety having at least the diameter of a methyl group was measurably permeant. Here, we show that, despite similar alkali cation permeability sequences for pro- and eu-karyotic channels (Finol-Urdaneta et al 2014 J Gen Physiol), relative permeabilities among organic ions (ammonium, hydrazinium, guanidinium and tetramethylammonium) are different. Using molecular dynamics simulations, we have asked to what extent 1d-pmfs based on the NavAb crystal structure might suggest a basis for NavBac selectivity among organic ions. Unlike eukaryotic channels, NavBac permeabilities do not show a size cut-off based on minimal cross-section, but are correlated with apparent binding energies in 1-dimensional potentials of mean force from simulations of single ions moving through the channel. In contrast, earlier analyses for eukaryotic Nav1s, suggest that differences among ion entry barriers are sufficient to account for relative permeabilities (Hille 1975 J Gen Physiol). We surmise that multi-ion occupancy and structural flexibility of Bac-Navs may also contribute to the observed and simulated functional differences. Meanwhile, we examined the consistency of our PMFs based on Zhu and Hummer's paper (Zhu & Hummer, 2011 J Comput Chem). The results indicate that it needs at least 10ns for particular windows to get accurate PMFs even for small molecules like ammonium.