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

Smith SS, Steinle ED, Meyerhoff ME, Dawson DC - J. Gen. Physiol. (1999)

Bottom Line: The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19.These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energy (the well depth) to be more negative.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel exhibits lyotropic anion selectivity. Anions that are more readily dehydrated than Cl exhibit permeability ratios (P(S)/P(Cl)) greater than unity and also bind more tightly in the channel. We compared the selectivity of CFTR to that of a synthetic anion-selective membrane [poly(vinyl chloride)-tridodecylmethylammonium 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 continuum electrostatic model suggested that both patterns could be understood in terms of the differences in the relative stabilization of anions by water and the polarizable interior of the channel or synthetic membrane. The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19. The model predicts that large anions, like SCN, although they experience weaker interactions (relative to Cl) with water and also with the channel, are more permeant 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 energy (the well depth) to be more negative. This simple selectivity mechanism that 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.

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(A) Energetic analysis of PVC-TDMAC membrane selectivity. The filled circles represent the equilibrium transfer energy [Δ(ΔG)trans] for each anion relative to the value of C(CN)3 plotted as function of reciprocal anion radius, 1/r (Table ), and the dashed line is the best fit to the points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using  and plotted versus 1/r. The dotted line is the relative solvation energy [/Δ(ΔG)solv/, C(CN)3 reference] calculated as Δ(ΔG)hyd − Δ(ΔG)trans. (A, inset) The free energy of transfer for a spherical test charge of 1-Å radius, plotted as a function of the dielectric constant of the medium to which the ion is being transferred from a vacuum according to . (B) Energetic analysis of CFTR permeability selectivity. The solid circles represent the relative peak height [Δ(ΔG)peak, C(CN)3 reference] calculated from the permeability ratios (Table ) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using  vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.
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Figure 3: (A) Energetic analysis of PVC-TDMAC membrane selectivity. The filled circles represent the equilibrium transfer energy [Δ(ΔG)trans] for each anion relative to the value of C(CN)3 plotted as function of reciprocal anion radius, 1/r (Table ), and the dashed line is the best fit to the points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using and plotted versus 1/r. The dotted line is the relative solvation energy [/Δ(ΔG)solv/, C(CN)3 reference] calculated as Δ(ΔG)hyd − Δ(ΔG)trans. (A, inset) The free energy of transfer for a spherical test charge of 1-Å radius, plotted as a function of the dielectric constant of the medium to which the ion is being transferred from a vacuum according to . (B) Energetic analysis of CFTR permeability selectivity. The solid circles represent the relative peak height [Δ(ΔG)peak, C(CN)3 reference] calculated from the permeability ratios (Table ) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.

Mentions: To understand the physical basis of the selectivity patterns common to CFTR and the PVC-TDMAC membrane, it was necessary to relate the energy differences associated with anion permeability ratios, relative anion binding affinities, and anion partitioning into the synthetic membrane to some physical property of the anions. As exemplified by the seminal work of Eisenman 1962 and the analysis of the acetylcholine receptor by Lewis and Stevens 1983, the natural choice for this parameter is ion size, expressed as the reciprocal of ionic radius, 1/r. This is so because the dominant contribution to the electrostatic free energy of a spherical ion varies with 1/r (Buckingham 1957; Bockris, and Reddy 1970). Fig. 3A and Fig. B, shows the results of such analysis for the PVC-TDMAC membrane and CFTR, respectively. In Fig. 3 A, the energy differences associated with anion partitioning into the PVC-TDMAC membrane obtained from Δ(ΔG)trans (see ) are plotted versus the reciprocal of ionic radius (Table ). In Fig. 3 B, the relative heights of the energy barriers associated with entering the CFTR channel obtained from permeability ratios (Table ) are plotted versus the reciprocal of the anionic radius. Because C(CN)3, the largest and most permeant ion, was chosen as the reference anion for both plots, for each anion, either the increase in equilibrium transfer energy (synthetic membrane) or the increase in barrier height (CFTR) relative to that seen by C(CN)3 is plotted versus 1/r. In both cases, the energy difference increases linearly with 1/r. Lewis and Stevens 1983 pointed out that the slope of this type of plot provides a quantitative measure of selectivity, and by that standard it is apparent that the synthetic membrane is approximately five times more selective than CFTR.


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

Smith SS, Steinle ED, Meyerhoff ME, Dawson DC - J. Gen. Physiol. (1999)

(A) Energetic analysis of PVC-TDMAC membrane selectivity. The filled circles represent the equilibrium transfer energy [Δ(ΔG)trans] for each anion relative to the value of C(CN)3 plotted as function of reciprocal anion radius, 1/r (Table ), and the dashed line is the best fit to the points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using  and plotted versus 1/r. The dotted line is the relative solvation energy [/Δ(ΔG)solv/, C(CN)3 reference] calculated as Δ(ΔG)hyd − Δ(ΔG)trans. (A, inset) The free energy of transfer for a spherical test charge of 1-Å radius, plotted as a function of the dielectric constant of the medium to which the ion is being transferred from a vacuum according to . (B) Energetic analysis of CFTR permeability selectivity. The solid circles represent the relative peak height [Δ(ΔG)peak, C(CN)3 reference] calculated from the permeability ratios (Table ) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using  vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.
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Related In: Results  -  Collection

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Figure 3: (A) Energetic analysis of PVC-TDMAC membrane selectivity. The filled circles represent the equilibrium transfer energy [Δ(ΔG)trans] for each anion relative to the value of C(CN)3 plotted as function of reciprocal anion radius, 1/r (Table ), and the dashed line is the best fit to the points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using and plotted versus 1/r. The dotted line is the relative solvation energy [/Δ(ΔG)solv/, C(CN)3 reference] calculated as Δ(ΔG)hyd − Δ(ΔG)trans. (A, inset) The free energy of transfer for a spherical test charge of 1-Å radius, plotted as a function of the dielectric constant of the medium to which the ion is being transferred from a vacuum according to . (B) Energetic analysis of CFTR permeability selectivity. The solid circles represent the relative peak height [Δ(ΔG)peak, C(CN)3 reference] calculated from the permeability ratios (Table ) plotted as function of reciprocal anion radius, 1/r (Table ). The dashed line is the best fit to the data points. The solid line is the relative hydration energy [/Δ(ΔG)hyd/, C(CN)3 reference] calculated using vs. 1/r. The dotted line is the apparent relative solvation energy [/Δ(ΔG)solv/] calculated by subtracting the best fit to the data points from /Δ(ΔG)hyd/.
Mentions: To understand the physical basis of the selectivity patterns common to CFTR and the PVC-TDMAC membrane, it was necessary to relate the energy differences associated with anion permeability ratios, relative anion binding affinities, and anion partitioning into the synthetic membrane to some physical property of the anions. As exemplified by the seminal work of Eisenman 1962 and the analysis of the acetylcholine receptor by Lewis and Stevens 1983, the natural choice for this parameter is ion size, expressed as the reciprocal of ionic radius, 1/r. This is so because the dominant contribution to the electrostatic free energy of a spherical ion varies with 1/r (Buckingham 1957; Bockris, and Reddy 1970). Fig. 3A and Fig. B, shows the results of such analysis for the PVC-TDMAC membrane and CFTR, respectively. In Fig. 3 A, the energy differences associated with anion partitioning into the PVC-TDMAC membrane obtained from Δ(ΔG)trans (see ) are plotted versus the reciprocal of ionic radius (Table ). In Fig. 3 B, the relative heights of the energy barriers associated with entering the CFTR channel obtained from permeability ratios (Table ) are plotted versus the reciprocal of the anionic radius. Because C(CN)3, the largest and most permeant ion, was chosen as the reference anion for both plots, for each anion, either the increase in equilibrium transfer energy (synthetic membrane) or the increase in barrier height (CFTR) relative to that seen by C(CN)3 is plotted versus 1/r. In both cases, the energy difference increases linearly with 1/r. Lewis and Stevens 1983 pointed out that the slope of this type of plot provides a quantitative measure of selectivity, and by that standard it is apparent that the synthetic membrane is approximately five times more selective than CFTR.

Bottom Line: The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19.These large anions also bind more tightly for the same reason: the reduced energy of hydration allows the net transfer energy (the well depth) to be more negative.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

ABSTRACT
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl channel exhibits lyotropic anion selectivity. Anions that are more readily dehydrated than Cl exhibit permeability ratios (P(S)/P(Cl)) greater than unity and also bind more tightly in the channel. We compared the selectivity of CFTR to that of a synthetic anion-selective membrane [poly(vinyl chloride)-tridodecylmethylammonium 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 continuum electrostatic model suggested that both patterns could be understood in terms of the differences in the relative stabilization of anions by water and the polarizable interior of the channel or synthetic membrane. The calculated energies of anion-channel interaction, derived from measurements of either permeability or binding, varied as a linear function of inverse ionic radius (1/r), as expected from a Born-type model of ion charging in a medium characterized by an effective dielectric constant of 19. The model predicts that large anions, like SCN, although they experience weaker interactions (relative to Cl) with water and also with the channel, are more permeant 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 energy (the well depth) to be more negative. This simple selectivity mechanism that 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.

Show MeSH
Related in: MedlinePlus