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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) Energetics of CFTR relative binding selectivity. The filled circles are the relative well depth [/Δ(ΔG)well/, C(CN)3 reference] calculated using the ratio of the apparent inhibition constants (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  plotted vs. 1/r for reference. Due to the fact that the measurements were made with respect to Cl (see materials and methods), it is not possible to calculate a value for Cl; however, the plot permits an extrapolation for Cl based on the size of the anion (highlighted with an arrow). (B) Anion-channel stabilization energies at the binding site plotted with respect to a vacuum reference phase. The filled circles are the well depths set by fixing the well depth for SCN at 12.5 kJ/mol (5.1 RT, based on the dissociation constant of 6.4 mM reported by Tabcharani et al. 1993) and adding the hydration energy plotted as function of reciprocal anion radius, 1/r. The dashed line is the best fit to the data points. The Cl point (○) shown is the well depth of 8.2 kJ/mol, based on the reported dissociation constant for Cl of 38 mM reported by Tabcharani et al. 1997, shown for comparison. The solid line is the hydration energy, /ΔGhyd/, calculated using  plotted vs. 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using  plotted vs. 1/r, as in Fig. 4. Note that values of transfer energy greater than the hydration energy reflect energetic wells, whereas values less than the hydration energy reflect energetic barriers.
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Figure 6: (A) Energetics of CFTR relative binding selectivity. The filled circles are the relative well depth [/Δ(ΔG)well/, C(CN)3 reference] calculated using the ratio of the apparent inhibition constants (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 plotted vs. 1/r for reference. Due to the fact that the measurements were made with respect to Cl (see materials and methods), it is not possible to calculate a value for Cl; however, the plot permits an extrapolation for Cl based on the size of the anion (highlighted with an arrow). (B) Anion-channel stabilization energies at the binding site plotted with respect to a vacuum reference phase. The filled circles are the well depths set by fixing the well depth for SCN at 12.5 kJ/mol (5.1 RT, based on the dissociation constant of 6.4 mM reported by Tabcharani et al. 1993) and adding the hydration energy plotted as function of reciprocal anion radius, 1/r. The dashed line is the best fit to the data points. The Cl point (○) shown is the well depth of 8.2 kJ/mol, based on the reported dissociation constant for Cl of 38 mM reported by Tabcharani et al. 1997, shown for comparison. The solid line is the hydration energy, /ΔGhyd/, calculated using plotted vs. 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using plotted vs. 1/r, as in Fig. 4. Note that values of transfer energy greater than the hydration energy reflect energetic wells, whereas values less than the hydration energy reflect energetic barriers.

Mentions: Fig. 6A and Fig. B, shows values for the binding energies derived from the comparative analysis of blockade of CFTR by halides and pseudohalides, which we presume to reflect the presence in the permeation path of at least one energy well. Fig. 6 A shows that the relative energies of binding, like the barriers to permeation, decrease with increasing values of 1/r. The implications of the variation in well depth depicted in Fig. 6 A are more readily apparent from a plot of estimated values for the anion–channel interaction energies calculated at the binding site with respect to a vacuum reference (Fig. 6 B). The values plotted in Fig. 6 B were calculated by fixing the well depth for SCN at 12.5 kJ/mol (5.1 RT) on the basis of the dissociation constant of 6.4 mM reported by Tabcharani et al. 1993, and adding the calculated hydration energy. The points for C(CN)3, Au(CN)2, N(CN)2, and N3 were determined by taking their values relative to SCN, and then adding the calculated hydration energy. The dashed line is the best fit to the data points. The predicted well depth for Cl is ∼6.5 kJ/mol, which agrees well with the value of 8.2 kJ/mol calculated from the dissociation constant of 38 mM reported by Tabcharani et al. 1997, which is shown as an open circle on the plot.


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) Energetics of CFTR relative binding selectivity. The filled circles are the relative well depth [/Δ(ΔG)well/, C(CN)3 reference] calculated using the ratio of the apparent inhibition constants (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  plotted vs. 1/r for reference. Due to the fact that the measurements were made with respect to Cl (see materials and methods), it is not possible to calculate a value for Cl; however, the plot permits an extrapolation for Cl based on the size of the anion (highlighted with an arrow). (B) Anion-channel stabilization energies at the binding site plotted with respect to a vacuum reference phase. The filled circles are the well depths set by fixing the well depth for SCN at 12.5 kJ/mol (5.1 RT, based on the dissociation constant of 6.4 mM reported by Tabcharani et al. 1993) and adding the hydration energy plotted as function of reciprocal anion radius, 1/r. The dashed line is the best fit to the data points. The Cl point (○) shown is the well depth of 8.2 kJ/mol, based on the reported dissociation constant for Cl of 38 mM reported by Tabcharani et al. 1997, shown for comparison. The solid line is the hydration energy, /ΔGhyd/, calculated using  plotted vs. 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using  plotted vs. 1/r, as in Fig. 4. Note that values of transfer energy greater than the hydration energy reflect energetic wells, whereas values less than the hydration energy reflect energetic barriers.
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Figure 6: (A) Energetics of CFTR relative binding selectivity. The filled circles are the relative well depth [/Δ(ΔG)well/, C(CN)3 reference] calculated using the ratio of the apparent inhibition constants (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 plotted vs. 1/r for reference. Due to the fact that the measurements were made with respect to Cl (see materials and methods), it is not possible to calculate a value for Cl; however, the plot permits an extrapolation for Cl based on the size of the anion (highlighted with an arrow). (B) Anion-channel stabilization energies at the binding site plotted with respect to a vacuum reference phase. The filled circles are the well depths set by fixing the well depth for SCN at 12.5 kJ/mol (5.1 RT, based on the dissociation constant of 6.4 mM reported by Tabcharani et al. 1993) and adding the hydration energy plotted as function of reciprocal anion radius, 1/r. The dashed line is the best fit to the data points. The Cl point (○) shown is the well depth of 8.2 kJ/mol, based on the reported dissociation constant for Cl of 38 mM reported by Tabcharani et al. 1997, shown for comparison. The solid line is the hydration energy, /ΔGhyd/, calculated using plotted vs. 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using plotted vs. 1/r, as in Fig. 4. Note that values of transfer energy greater than the hydration energy reflect energetic wells, whereas values less than the hydration energy reflect energetic barriers.
Mentions: Fig. 6A and Fig. B, shows values for the binding energies derived from the comparative analysis of blockade of CFTR by halides and pseudohalides, which we presume to reflect the presence in the permeation path of at least one energy well. Fig. 6 A shows that the relative energies of binding, like the barriers to permeation, decrease with increasing values of 1/r. The implications of the variation in well depth depicted in Fig. 6 A are more readily apparent from a plot of estimated values for the anion–channel interaction energies calculated at the binding site with respect to a vacuum reference (Fig. 6 B). The values plotted in Fig. 6 B were calculated by fixing the well depth for SCN at 12.5 kJ/mol (5.1 RT) on the basis of the dissociation constant of 6.4 mM reported by Tabcharani et al. 1993, and adding the calculated hydration energy. The points for C(CN)3, Au(CN)2, N(CN)2, and N3 were determined by taking their values relative to SCN, and then adding the calculated hydration energy. The dashed line is the best fit to the data points. The predicted well depth for Cl is ∼6.5 kJ/mol, which agrees well with the value of 8.2 kJ/mol calculated from the dissociation constant of 38 mM reported by Tabcharani et al. 1997, which is shown as an open circle on the plot.

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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Related in: MedlinePlus