| Sumario: | Monovalent Na and K ion channels, specialized pore-forming proteins that play crucial biological roles such as controlling cardiac, skeletal, and smooth muscle contraction, are characterized by a remarkable metal selectivity, conducting the native cation while rejecting its monovalent contender and other ions present in the cellular/exiracellular milieu. Compared to K channels, the principles governing Na vs K selectivity in both epithelial and voltage-gated Na channels are much less well understood due mainly to the lack of high-resolution 3D structures. Thus, many questions remain. It is not clear if the serines lining the pore of epithelial Na channel bind to the metal cation via their backbone or side chain 0 atoms and why substituting the Lys lining the pore of voltage-gated Na channels to another residue such as Arg drastically reduces or even reverses the Na1iK selectivity. This work systematically evaluates the effects of various factors such as (i) the number, chemical type, and charge of the pore's coordinating groups, (ii) the hydration number and coordination number of the metal cation, and (iii) the solvent exposure and the size/rigidity of the pore on the Na vs K selectivity in model Na channel selectivity filters (the narrowest part of the pore) using a combined density functional theory/continuum dielectric approach. The results reveal that the Na channel's selectivity for Na over K increases if (1) the pore provides three rather than four protein ligands to coordinate to the metal ion, (2) the protein ligands have strong charge-donating ability such as Asp/Glu carboxylate or backbone carbonyl groups, (3) the passing Na is bare or less well hydrated inside the filter than the competing K, and (4) the pore is relatively rigid, constricted, and solvent exposed. They also reveal that factors favoring Na/K1 selectivity in Na channels generally disfavor K/Na selectivity in K channels and vice versa. The different selectivity principles for the K and Na channels are consistent with the different architecture, composition, and properties of their selectivity filters. They provide clues to the metal-binding site structure in the selectivity filters of epithelial and voltage-gated Na channels.
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