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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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Model for permeation in Cl channels that exhibit lyotropic selectivity. (A) A channel that does not bind ions. An anion is indicated in three locations along with its inner sphere water molecules. (B) The inner “lining” of the wtCFTR pore, with its anion binding site, suspended in water, with an anion in the proposed narrow region in which elements of the pore wall make inner sphere contact with the anion. (C) The wtCFTR channel with its anion binding site in a lipid bilayer. (D) The energetics of transfer. The solid trapezoidal line represents the energetic expense associated with partitioning into a “polarizable” tunnel embedded in a bilayer, envisioned in A. The dashed line represents the energetic well seen by an anion in the narrow region of the pore wall in free solution, as envisioned in B. The dotted line represents the profile of the total free energy (A + B) associated with traversing the wtCFTR channel embedded in a bilayer. The well depth and peak height are predicted to change in a parallel fashion due to the anion size-dependent changes in the free energy, which is shown in E for Cl (solid line) and a larger anion (dashed line), such as SCN. Anions that enter the channel more readily also bind more tightly.
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Figure 8: Model for permeation in Cl channels that exhibit lyotropic selectivity. (A) A channel that does not bind ions. An anion is indicated in three locations along with its inner sphere water molecules. (B) The inner “lining” of the wtCFTR pore, with its anion binding site, suspended in water, with an anion in the proposed narrow region in which elements of the pore wall make inner sphere contact with the anion. (C) The wtCFTR channel with its anion binding site in a lipid bilayer. (D) The energetics of transfer. The solid trapezoidal line represents the energetic expense associated with partitioning into a “polarizable” tunnel embedded in a bilayer, envisioned in A. The dashed line represents the energetic well seen by an anion in the narrow region of the pore wall in free solution, as envisioned in B. The dotted line represents the profile of the total free energy (A + B) associated with traversing the wtCFTR channel embedded in a bilayer. The well depth and peak height are predicted to change in a parallel fashion due to the anion size-dependent changes in the free energy, which is shown in E for Cl (solid line) and a larger anion (dashed line), such as SCN. Anions that enter the channel more readily also bind more tightly.

Mentions: Consider first a channel that does not bind anions (Fig. 8 A). It is useful to envision permeant anions in the bulk solution as coordinated by an inner sphere of water molecules and surrounded by an outer sphere or shell that is the remainder of the bulk solution (Sharp and Honig 1990; Andersen and Koeppe 1992; Marcus 1994). Upon colliding with the mouth of the channel, the anion and channel form a transition state complex that leads to the anion, along with most of its inner shell water, residing within the channel. In this state, the channel, to a first approximation, has replaced the outer shell waters (i.e., the bulk solution), but the inner sphere waters remain associated with the anion. The energy profile expected for the process is depicted as the trapezoidal line in Fig. 8 D and represents an equilibrium transfer free energy (reflected in the partition coefficient, β) that, for Cl, would be unfavorable by ∼6 RT (see results) due to the fact that the effective dielectric constant of the channel protein, the lipid membrane, and surrounding water is somewhat less than that of the outer sphere of water molecules in bulk solution. This represents the energy barrier seen by an anion entering the channel.


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

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

Model for permeation in Cl channels that exhibit lyotropic selectivity. (A) A channel that does not bind ions. An anion is indicated in three locations along with its inner sphere water molecules. (B) The inner “lining” of the wtCFTR pore, with its anion binding site, suspended in water, with an anion in the proposed narrow region in which elements of the pore wall make inner sphere contact with the anion. (C) The wtCFTR channel with its anion binding site in a lipid bilayer. (D) The energetics of transfer. The solid trapezoidal line represents the energetic expense associated with partitioning into a “polarizable” tunnel embedded in a bilayer, envisioned in A. The dashed line represents the energetic well seen by an anion in the narrow region of the pore wall in free solution, as envisioned in B. The dotted line represents the profile of the total free energy (A + B) associated with traversing the wtCFTR channel embedded in a bilayer. The well depth and peak height are predicted to change in a parallel fashion due to the anion size-dependent changes in the free energy, which is shown in E for Cl (solid line) and a larger anion (dashed line), such as SCN. Anions that enter the channel more readily also bind more tightly.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2230651&req=5

Figure 8: Model for permeation in Cl channels that exhibit lyotropic selectivity. (A) A channel that does not bind ions. An anion is indicated in three locations along with its inner sphere water molecules. (B) The inner “lining” of the wtCFTR pore, with its anion binding site, suspended in water, with an anion in the proposed narrow region in which elements of the pore wall make inner sphere contact with the anion. (C) The wtCFTR channel with its anion binding site in a lipid bilayer. (D) The energetics of transfer. The solid trapezoidal line represents the energetic expense associated with partitioning into a “polarizable” tunnel embedded in a bilayer, envisioned in A. The dashed line represents the energetic well seen by an anion in the narrow region of the pore wall in free solution, as envisioned in B. The dotted line represents the profile of the total free energy (A + B) associated with traversing the wtCFTR channel embedded in a bilayer. The well depth and peak height are predicted to change in a parallel fashion due to the anion size-dependent changes in the free energy, which is shown in E for Cl (solid line) and a larger anion (dashed line), such as SCN. Anions that enter the channel more readily also bind more tightly.
Mentions: Consider first a channel that does not bind anions (Fig. 8 A). It is useful to envision permeant anions in the bulk solution as coordinated by an inner sphere of water molecules and surrounded by an outer sphere or shell that is the remainder of the bulk solution (Sharp and Honig 1990; Andersen and Koeppe 1992; Marcus 1994). Upon colliding with the mouth of the channel, the anion and channel form a transition state complex that leads to the anion, along with most of its inner shell water, residing within the channel. In this state, the channel, to a first approximation, has replaced the outer shell waters (i.e., the bulk solution), but the inner sphere waters remain associated with the anion. The energy profile expected for the process is depicted as the trapezoidal line in Fig. 8 D and represents an equilibrium transfer free energy (reflected in the partition coefficient, β) that, for Cl, would be unfavorable by ∼6 RT (see results) due to the fact that the effective dielectric constant of the channel protein, the lipid membrane, and surrounding water is somewhat less than that of the outer sphere of water molecules in bulk solution. This represents the energy barrier seen by an anion entering the channel.

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