Factors controlling the selectivity for Na+ over Mg2+ in sodium transporters and enzymes

Abstract

Na⁺ and Mg²⁺ play different crucial roles in biological systems. Both cations are present in comparable amounts in the cytosol, but how monovalent Na⁺ can compete with the divalent Mg²⁺, which can better accept charge from negatively charged ligands, in sodium transporters/enzymes has not been investigated. Hence, it is not clear how Na⁺ and Mg²⁺-binding sites have evolved to discriminate the “right” cation among non-cognate ones from the surrounding milieu and the physical basis governing the selectivity for Na⁺ over Mg²⁺. The results, which are consistent with available experimental data, reveal that in proteins, the selectivity for Na⁺ over Mg²⁺ in sodium-binding sites stem mainly from the size, charge, and charge-accepting ability differences between Na⁺ and Mg²⁺. A protein could achieve Na⁺ selectivity by (i) reducing the number of metal-ligating ligands, (ii) maintaining an optimal balance of different ligating-strength ligands whose interactions in the metal-binding site would favor Na⁺ over rival mono/divalent cations, (iii) increasing the solvent exposure of the metal-binding site, or (iv) increasing binding site rigidity forcing Mg²⁺ to adopt the coordination distances/geometry of Na⁺. Sodium-binding proteins use one or more of these factors to achieve Na⁺ selectivity.