Bases of Bacterial Sodium Channel Selectivity Among Organic Cations

Yibo Wang, Rocio K. Finol-Urdaneta, Van Anh Ngo, Robert J. French, Sergei Yu Noskov

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Abstract

Hille’s (1971) seminal study of organic cation selectivity of eukaryotic voltage-gated sodium channels showed a sharp size cut-off for ion permeation, such that no ion possessing a methyl group was permeant. Using the prokaryotic channel, NaChBac, we found some similarity and two peculiar differences in the selectivity profiles for small polyatomic cations. First, we identified a diverse group of minimally permeant cations for wildtype NaChBac, ranging in sizes from ammonium to guanidinium and tetramethylammonium; and second, for both ammonium and hydrazinium, the charge-conserving selectivity filter mutation (E191D) yielded substantial increases in relative permeability (PX/PNa). The relative permeabilities varied inversely with relative Kd calculated from 1D Potential of Mean Force profiles (PMFs) for the single cations traversing the channel. Several of the cations bound more strongly than Na+, and hence appear to act as blockers, as well as charge carriers. Consistent with experimental observations, the E191D mutation had little impact on Na+ binding to the selectivity filter, but disrupted the binding of ammonium and hydrazinium, consequently facilitating ion permeation across the NaChBac-like filter. We concluded that for prokaryotic sodium channels, a fine balance among filter size, binding affinity, occupancy, and flexibility seems to contribute to observed functional differences.

Original languageEnglish
Article number15260
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

Funding

This work was supported by grants from the Natural Sciences and Engineering Research Council (Canada) to S.Y.N. (NSERC RGPIN-315019) and the Alberta Innovates Technical Futures Strategic Chair in (Bio)Molecular Simulations. V.A.N. was financially supported by Postdoctoral Fellowships (AIHS and CIHR) during 2015–2018, and by LANL Director’s Fellowship during 2018–2021 (V.A.N.). The classification number for this publication issued by LANL is LA-UR-19-29893. The experiments and simulations reported here also featured in the doctoral thesis of Y.W. https://prism.ucalgary.ca/handle/11023/3077. All of the computations were performed on the West-Grid/ Compute Canada facilities, and the University of Calgary TNK and GlaDos clusters acquired with direct support by the Canada Foundation for Innovation and NSERC RTI awards.

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