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. 2011 Jun;137(6):479-88.
doi: 10.1085/jgp.201010579.

Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport

Sameer Varma  1 , David M Rogers, Lawrence R Pratt, Susan B Rempe
Affiliations

Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport

Sameer Varma et al. J Gen Physiol. 2011 Jun.

Erratum in

  • J Gen Physiol. 2011 Aug;138(2):279
No abstract available

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Figures

Figure 1.
Figure 1.
Representative binding modes of Na+ and K+ ions in structural motifs of K+-selective membrane transport molecules. (Note that only two units from the tetrameric selectivity filters are shown for clarity.) (A) The selectivity filter of KcsA (Zhou et al., 2001) adopts different configurations under conditions of high and (B) low K+ concentrations, presenting K+ with different sets of binding modes. (C) Under rare conditions when Na+ binds to the KcsA filter, Na+ prefers a binding site different from K+ (Nimigean and Miller, 2002; Shrivastava et al., 2002; Lockless et al., 2007; Thompson et al., 2009). (D) The bacterial NaK channel, which belongs to the family of CNG channels, has a selectivity filter architecture similar to KcsA, but is only weakly selective for K+. Initially, low temperature x-ray data suggested binding modes for K+ that are identical to Na+. (E) Newer higher resolution crystallographic studies show more variety in Na+ binding, attributing electron density at the S3 site to competitive binding of a contaminant (orange) with Na+, with other Na+-binding sites between planes of carbonyl or hydroxyl oxygens (Alam and Jiang, 2009). (F) In comparison to KcsA and the NaK channel, the K+-selective bacterial toxin molecule (Dobler, 1981), valinomycin, binds K+ differently, using six (or fewer) carbonyl oxygens, instead of eight (or fewer) as in KcsA and NaK.
Figure 2.
Figure 2.
Experimental estimates of selectivity free energy, ΔΔG=ΔGK→Na−ΔGK→Nabulk, for different organic solvents with respect to bulk liquid water (Cox and Parker, 1973; Marcus, 1983; Schmid et al., 2000; Yu et al., 2010a). For these estimates, GX=(∂G/∂nX)T,P is the partial molar Gibbs free energy for ion X in the specified medium relative to an ideal standard state, so that ΔG vanishes when ion–medium interactions vanish.
Figure 3.
Figure 3.
Dependence of K+/Na+ selectivity on ligand composition in eight-ligand binding site models where ligand distances are generically confined to be within a 3.5-Å radius of the central ion. (A) The conventional field strength trend observed by Eisenman is illustrated by the dependence of selectivity, ΔΔG, on the dipole moment of linear ligands. Results were taken from binding site models described previously (red triangles, Noskov et al., 2004; black triangles, Thomas et al., 2007; circles were calculated with standard [black] or modified [red] CHARMM parameters, Bostick et al., 2009). Filled circles show results from a half-harmonic boundary restraint, and open circles show the corresponding Lennard-Jones restraint. The conventional field strength trend (dashed line) is independent of these different restraints. (B) Dependence of K+/Na+ selectivity, ΔΔG, on incremental replacement of carbonyl-like dipolar groups with water molecules. In contrast to the trend in A, recent work predicted a systematic loss of selectivity for each water molecule that replaces a carbonyl group (∼1.8 kcal/mol per water using the CHARMM force field) (Noskov and Roux, 2006, 2007). The red line illustrates this trend toward Na+ selectivity, which supports the revised field strength model. Data from subsequent calculations (Bostick et al., 2009), using the same force field and either a Lennard-Jones (LJ, black solid lines/circles) or a half-harmonic (black dashed lines and open circles) confining potential, do not eliminate the K+ selectivity.
Figure 4.
Figure 4.
Results from binding site models demonstrating the effect of an external field, in the form of an ion coordination number constraint, on K+/Na+ selectivity. Calculations were performed using the AMOEBA polarizable force field (Bostick and Brooks, 2010). (A) ΔΔG versus the number of included molecules, NI, in gas-phase clusters around K+ and Na+ in the absence of a constraint on coordination. As NI increases, the observed selectivity approaches values expected for bulk liquids (for water, ΔΔG ≈ 0; for formamide/NMA, ΔΔG < 0). Note that the number of included molecules, NI, is not necessarily equal to the number of coordinating molecules, NC, because of the absence of a coordination constraint. (B) ΔΔG versus the number of molecules, NC, directly coordinating K+ and Na+. In agreement with quantum mechanical calculations (Varma and Rempe, 2007, 2008), ΔΔG is larger in the water-based models (blue) than in the carbonyl-based models (black and red). Because of the presence of an external field (half-harmonic confinement) that imposes a specific coordination number, K+ selectivity is observed for seven or more ligands. In the models that coordinate K+ or Na+ with carbonyl ligands, K+ selectivity is determined by the external field rather than the ligand identity (NMA, formamide, and water) because the binding site models are Na+ selective in the absence of the constraint on coordination number, NC. (C) Contributions from specified individual components of the selectivity free energy (Eq. 2) in models composed of eight formamide molecules: ligand–ligand interactions, ΔUK→NaLL, ion–ligand interactions, ΔUK→NaIL, intramolecular interactions, ΔUK→Naintra, and entropy −TΔSK→Na. In the case considered here, the contribution from the external field, ΔUK→Nafield≈0, is negligible. In the absence of the field (left), the components yield net Na+ selectivity (ΔΔG < 0). When a field enforces eightfold coordination, the distribution of these individual components changes, producing net K+ selectivity (ΔΔG > 0). Thus, the redistribution of the individual components, and therefore the net K+ selectivity, is an effect of the applied external field.
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References

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