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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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Energetics of CFTR permeability selectivity expressed with respect to a vacuum reference phase. The filled circles represent the relative peak heights (ΔGpeak, vacuum reference) calculated from the permeability ratios (Table ) and plotted as a function of reciprocal anion radius, 1/r (Table ). The solid line is the hydration energy, /ΔGhyd/, calculated using , and plotted versus 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using  vs. 1/r. The dashed line is the predicted peak barrier height, ΔGpeak, calculated from the difference between the hydration energy and the solvation energy (ΔGsolv − ΔGhyd).
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Figure 4: Energetics of CFTR permeability selectivity expressed with respect to a vacuum reference phase. The filled circles represent the relative peak heights (ΔGpeak, vacuum reference) calculated from the permeability ratios (Table ) and plotted as a function of reciprocal anion radius, 1/r (Table ). The solid line is the hydration energy, /ΔGhyd/, calculated using , and plotted versus 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using vs. 1/r. The dashed line is the predicted peak barrier height, ΔGpeak, calculated from the difference between the hydration energy and the solvation energy (ΔGsolv − ΔGhyd).

Mentions: Fig. 3 B shows the behavior of Δ(ΔGpeak), Δ(ΔGhyd), and Δ(ΔGsolv) for CFTR. It is immediately apparent from Fig. 3 B that the modest permeability selectivity of CFTR can be attributed to the fact that the energies of hydration and solvation differ very little over the range of anion sizes examined. In other words, a visiting anion is solvated within the CFTR pore nearly as well as it is in bulk water. Accordingly, the solvation energy predicts an effective dielectric constant within the pore of ∼19. The near identity of the value of ΔGhyd and ΔGsolv justifies treating the energies associated with anion entry as a near equilibrium process. The point is made more explicitly in Fig. 4, in which are shown the predicted values expressed with respect to a vacuum reference phase for ΔGpeak, ΔGhyd, and ΔGsolv, calculated using a value of 19 for the effective dielectric constant within the channel. This plot predicts a peak energy for Cl of 14.5 kJ/mol (5.86 RT), which agrees well with the values derived by Linsdell et al. 1997a for a multi-site model, and is about half the value of 27.8 kJ/mol (11.2 RT) predicted from a symmetric two-barrier, one-site model using a well depth of 8.2 kJ/mol (3.3 RT) (based on the dissociation constant of 38 mM for chloride as determined by Tabcharani et al. 1997) and constraining the single channel conductance to 10 pS (Dawson et al. 1999). Although these values are likely to be significantly affected by the ambiguity as to the appropriate value for the prefactor in the Eyring rate equations (Andersen 1999; Levitt 1999; Nonner et al. 1999), it is apparent that the absolute barrier heights predicted from continuum analysis fall in a range consistent with observed transport rates. The error in the prefactor incurred by using kT/h has been estimated, using a discrete approximation to a continuum model, to be of the order of 102, which would translate into an error in the calculated value of ΔG of ∼4.6 RT (Andersen and Koeppe 1992).


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

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

Energetics of CFTR permeability selectivity expressed with respect to a vacuum reference phase. The filled circles represent the relative peak heights (ΔGpeak, vacuum reference) calculated from the permeability ratios (Table ) and plotted as a function of reciprocal anion radius, 1/r (Table ). The solid line is the hydration energy, /ΔGhyd/, calculated using , and plotted versus 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using  vs. 1/r. The dashed line is the predicted peak barrier height, ΔGpeak, calculated from the difference between the hydration energy and the solvation energy (ΔGsolv − ΔGhyd).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230651&req=5

Figure 4: Energetics of CFTR permeability selectivity expressed with respect to a vacuum reference phase. The filled circles represent the relative peak heights (ΔGpeak, vacuum reference) calculated from the permeability ratios (Table ) and plotted as a function of reciprocal anion radius, 1/r (Table ). The solid line is the hydration energy, /ΔGhyd/, calculated using , and plotted versus 1/r. The dotted line is the solvation energy, /ΔGsolv/, calculated for a homogenous medium with a dielectric constant of 19 using vs. 1/r. The dashed line is the predicted peak barrier height, ΔGpeak, calculated from the difference between the hydration energy and the solvation energy (ΔGsolv − ΔGhyd).
Mentions: Fig. 3 B shows the behavior of Δ(ΔGpeak), Δ(ΔGhyd), and Δ(ΔGsolv) for CFTR. It is immediately apparent from Fig. 3 B that the modest permeability selectivity of CFTR can be attributed to the fact that the energies of hydration and solvation differ very little over the range of anion sizes examined. In other words, a visiting anion is solvated within the CFTR pore nearly as well as it is in bulk water. Accordingly, the solvation energy predicts an effective dielectric constant within the pore of ∼19. The near identity of the value of ΔGhyd and ΔGsolv justifies treating the energies associated with anion entry as a near equilibrium process. The point is made more explicitly in Fig. 4, in which are shown the predicted values expressed with respect to a vacuum reference phase for ΔGpeak, ΔGhyd, and ΔGsolv, calculated using a value of 19 for the effective dielectric constant within the channel. This plot predicts a peak energy for Cl of 14.5 kJ/mol (5.86 RT), which agrees well with the values derived by Linsdell et al. 1997a for a multi-site model, and is about half the value of 27.8 kJ/mol (11.2 RT) predicted from a symmetric two-barrier, one-site model using a well depth of 8.2 kJ/mol (3.3 RT) (based on the dissociation constant of 38 mM for chloride as determined by Tabcharani et al. 1997) and constraining the single channel conductance to 10 pS (Dawson et al. 1999). Although these values are likely to be significantly affected by the ambiguity as to the appropriate value for the prefactor in the Eyring rate equations (Andersen 1999; Levitt 1999; Nonner et al. 1999), it is apparent that the absolute barrier heights predicted from continuum analysis fall in a range consistent with observed transport rates. The error in the prefactor incurred by using kT/h has been estimated, using a discrete approximation to a continuum model, to be of the order of 102, which would translate into an error in the calculated value of ΔG of ∼4.6 RT (Andersen and Koeppe 1992).

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