Cystic fibrosis transmembrane conductance regulator: Physical basis for lyotropic anion selectivity patterns

The cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel e xhibits lyotropic anion selectivity. Anions that are more readily dehydrate d than Cl exhibit permeability ratios (P-S/P-Cl) greater than unity and als o bind more tightly in the channel. We compared the selectivity of CFTR to that of a synthetic anion-selective membrane [poly(vinyl chloride)-tridodec ylmethylammonium chloride; PVC-TDMAC] for which the nature of the physical process that governs the anion-selective response is more readily apparent. The permeability and binding selectivity patterns of CFTR differed only by a multiplicative constant from that of the PVC-TDMAC membrane; and a conti nuum electrostatic model suggested that both patterns could be understood i n terms of the differences in the relative stabilization of anions by water and the polarizable interior of the channel or synthetic membrane. The cal culated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ion ic radius (1/r), as expected from a Born-type model of ion charging in a me dium characterized by an effective dielectric constant of 19. The model pre dicts that large anions, like SCN, although they experience weaker interact ions (relative to Cl) with water and also with the channel, are more permea nt than Cl because anion-water energy is a steeper function of 1/r than is the anion-channel energy. These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energ y (the well depth) to be more negative. This simple selectivity mechanism t hat governs permeability and binding acts to optimize the function of CFTR as a Cl filter. Anions that are smaller (more difficult to dehydrate) than Cl are energetically retarded from entering the channel, while the larger ( more readily dehydrated) anions are retarded in their passage by "sticking" within the channel.