Tuning ion coordination architectures to enable selective partitioning

Abstract

K+ ions seemingly permeate K-channels rapidly because channel binding sites mimic coordination of K+ ions in water. Highly selective ion discrimination should occur when binding sites form rigid cavities that match K+, but not the smaller Na+, ion size or when binding sites are composed of specific chemical groups. Although conceptually attractive, these views cannot account for critical observations: 1), K+ hydration structures differ markedly from channel binding sites; 2), channel thermal fluctuations can obscure sub-Angström differences in ion sizes; and 3), chemically identical binding sites can exhibit diverse ion selectivities. Our quantum mechanical studies lead to a novel paradigm that reconciles these observations. We find that K-channels utilize a "phase-activated" mechanism where the local environment around the binding sites is tuned to sustain high coordination numbers (>6) around K+ ions, which otherwise are rarely observed in liquid water. When combined with the field strength of carbonyl ligands, such high coordinations create the electrical scenario necessary for rapid and selective K+ partitioning. Specific perturbations to the local binding site environment with respect to strongly selective K-channels result in altered K+/Na+ selectivities.

FIGURE 1

K⁺ ion coordination in selectivity filters of K-channels is markedly different from that in bulk water. KcsA, for example, offers three binding sites for K⁺ ions (2), S1–S3, where it coordinates with the ion using eight of its backbone carbonyl oxygen atoms (highlighted in red) at an average distance of 2.8 Å. In contrast, in a 40-ps-long AIMD (PW91) simulation of K⁺ ion in bulk water (generated by extending the previously reported (8) 14-ps-long trajectory), only four water molecules are seen most tightly bound to the K⁺ ion at an average distance of 2.8 Å. These four water molecules correspond to the maximum number that contribute to the principle maxima of the radial distribution function (g(r)); the fifth and the sixth nearest waters statistically do not contribute to the peak of the principal maxima; whereas the seventh and the eighth nearest waters are seldom seen within the canonical inner coordination shell (gray area) of the ion.

FIGURE 2

Different eightfold coordinated complexes of K⁺ ions considered in this investigation. ΔΔG refers to the free energy of partitioning a K⁺ ion from liquid water (reference environment) into the respective eightfold coordinated chemistries embedded in a quasiliquid phase. The interligand H-bonds are depicted using dashed lines connecting the hydrogen (white) and oxygen atoms (red). The chemistry and architecture that favors K⁺ ion partitioning precisely matches the binding sites S1–S3 found in the selectivity filters of K-channels.

FIGURE 3

(a) Phase diagram illustrating the structural and thermochemical effects of transferring Na⁺ and K⁺ ions from one combination of chemistry, architecture, and phase into another. The absolute free energies of solvating ions in these combinations can be inferred from the scale on the y axes of the plot, and the coordination numbers corresponding to these free energies are indicated in brackets. The hydration free energies of Na⁺ and K⁺ ions (n = 4) are also indicated as dashed lines, colored red and green, respectively. The open symbol enclosed in a dashed box denotes the only case where ligands are held rigid. This particular case represents the minimum of the cavity size-dependent K⁺/Na⁺ selectivity (∼10 kcal/mol) conferred by the chemistry of eight carbonyl ligands from four glycine dipeptide molecules arranged in a skewed cubic architecture, as estimated using the data in plot (b). From plot b, we see that irrespective of cavity size, measured as the distance between furthest oxygen atoms, the K⁺/Na⁺ ion selectivity conferred by this eightfold coordination is maintained. Since these values correspond to the lowest energy positions of the Na⁺ ions in the cavities, a choice of any other position for the ion will also result in K⁺/Na⁺ selectivity.