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Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport.

Varma S, Rogers DM, Pratt LR, Rempe SB - J. Gen. Physiol. (2011)

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Affiliation: Department of Biological, Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, USA.

ABSTRACT

The advent of atomic resolution structures of ion-selective channels made possible the transition from black box models to molecular descriptions for considering the design principles underlying selectivity in a flexible selectivity filter. Simple theoretical models applied to interpret the complex behaviors observed in whole molecule experiments and molecular simulations led to suggestions that ligand type is of primary importance in determining selectivity. As discussed in this Perspective, this view is incomplete. Models that focus on chemical forces as a primary design principle do not explain why carbonyl ligands produce K+ selectivity in eightfold K+ channel–binding sites, but yield Na+ selectivity in liquid analogues (Fig. 2). Additionally, these models have not explained why chemically identical binding sites in the strongly selective KcsA channel show significantly different selectivities in simulations of whole channels. The same question applies to NaK channels, which lack selectivity despite sharing two chemically identical binding sites with strongly selective K+ channels. We are left with the conclusion that ion selectivity requires consideration of both ligand characteristics and the forces influencing binding site composition and structure.

Recent simulations support the view that interactions with the more distant environment of the membrane transport molecule can modify properties of the binding site and influence selective binding. In the case of K+ channels, restricted carbonyl motion or a decrease in their availability to the protein environment can drive up ion coordination numbers in the selectivity filter, leading to K+ selectivity. A snug fit as in valinomycin can be enforced by an environment that stabilizes intra-molecular hydrogen bonding, achieving selectivity without over-coordination through a constraint on cavity size. The importance of environmental controls on binding sites has since been recognized in several recent works (see, for example, Fowler et al., 2008; Miloshevsky and Jordan, 2008; Vora et al., 2008; Dixit et al., 2009; Dudev and Lim, 2009; Yu and Roux, 2009; Yu et al., 2009, 2010b; Roux, 2010; Rogers and Rempe, 2011). This Perspective provides a foundation necessary for understanding the more complex behavior of selective ion transport through membranes.

This Perspectives series includes articles by Andersen, Alam and Jiang, Nimigean and Allen, Roux et al., and Dixit and Asthagiri.

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Results from binding site models demonstrating the effect of an external field, in the form of an ion coordination number constraint, on K+/Na+ selectivity. Calculations were performed using the AMOEBA polarizable force field (Bostick and Brooks, 2010). (A) ΔΔG versus the number of included molecules, NI, in gas-phase clusters around K+ and Na+ in the absence of a constraint on coordination. As NI increases, the observed selectivity approaches values expected for bulk liquids (for water, ΔΔG ≈ 0; for formamide/NMA, ΔΔG < 0). Note that the number of included molecules, NI, is not necessarily equal to the number of coordinating molecules, NC, because of the absence of a coordination constraint. (B) ΔΔG versus the number of molecules, NC, directly coordinating K+ and Na+. In agreement with quantum mechanical calculations (Varma and Rempe, 2007, 2008), ΔΔG is larger in the water-based models (blue) than in the carbonyl-based models (black and red). Because of the presence of an external field (half-harmonic confinement) that imposes a specific coordination number, K+ selectivity is observed for seven or more ligands. In the models that coordinate K+ or Na+ with carbonyl ligands, K+ selectivity is determined by the external field rather than the ligand identity (NMA, formamide, and water) because the binding site models are Na+ selective in the absence of the constraint on coordination number, NC. (C) Contributions from specified individual components of the selectivity free energy (Eq. 2) in models composed of eight formamide molecules: ligand–ligand interactions,  ion–ligand interactions,  intramolecular interactions,  and entropy  In the case considered here, the contribution from the external field,  is negligible. In the absence of the field (left), the components yield net Na+ selectivity (ΔΔG < 0). When a field enforces eightfold coordination, the distribution of these individual components changes, producing net K+ selectivity (ΔΔG > 0). Thus, the redistribution of the individual components, and therefore the net K+ selectivity, is an effect of the applied external field.
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fig4: Results from binding site models demonstrating the effect of an external field, in the form of an ion coordination number constraint, on K+/Na+ selectivity. Calculations were performed using the AMOEBA polarizable force field (Bostick and Brooks, 2010). (A) ΔΔG versus the number of included molecules, NI, in gas-phase clusters around K+ and Na+ in the absence of a constraint on coordination. As NI increases, the observed selectivity approaches values expected for bulk liquids (for water, ΔΔG ≈ 0; for formamide/NMA, ΔΔG < 0). Note that the number of included molecules, NI, is not necessarily equal to the number of coordinating molecules, NC, because of the absence of a coordination constraint. (B) ΔΔG versus the number of molecules, NC, directly coordinating K+ and Na+. In agreement with quantum mechanical calculations (Varma and Rempe, 2007, 2008), ΔΔG is larger in the water-based models (blue) than in the carbonyl-based models (black and red). Because of the presence of an external field (half-harmonic confinement) that imposes a specific coordination number, K+ selectivity is observed for seven or more ligands. In the models that coordinate K+ or Na+ with carbonyl ligands, K+ selectivity is determined by the external field rather than the ligand identity (NMA, formamide, and water) because the binding site models are Na+ selective in the absence of the constraint on coordination number, NC. (C) Contributions from specified individual components of the selectivity free energy (Eq. 2) in models composed of eight formamide molecules: ligand–ligand interactions, ion–ligand interactions, intramolecular interactions, and entropy In the case considered here, the contribution from the external field, is negligible. In the absence of the field (left), the components yield net Na+ selectivity (ΔΔG < 0). When a field enforces eightfold coordination, the distribution of these individual components changes, producing net K+ selectivity (ΔΔG > 0). Thus, the redistribution of the individual components, and therefore the net K+ selectivity, is an effect of the applied external field.

Mentions: Simulations of binding site models illustrate the consequences of constraints on coordination (Fig. 4). Coordination by five or six carbonyl oxygen atoms typically provides the weak selectivity observed in bulk liquids (Fig. 2), whereas strong K+ selectivity is associated with seven and eight coordinate complexes that resemble K+ channel architectures (Figs. 1 A and 4 B). In the absence of external forces imposing over-coordination, carbonyl ligands naturally assume a lower coordination number around each ion and K+/Na+ selectivity is lost (Fig. 4 A). Quantum mechanical studies of a model binding site composed of diglycine molecules show the same trends with Na+ binding (Varma and Rempe, 2007). These results support the argument that an environment that achieves high coordination numbers results in K+/Na+ selectivity, whereas an environment that permits relaxed coordination numbers produces lower selectivity. Note that this does not suggest that selectivity, in general, is solely controlled by coordination number: other types of constraints on an ion-bound complex can also play a role in selectivity, and ligand chemistry remains an important modulatory factor.


Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport.

Varma S, Rogers DM, Pratt LR, Rempe SB - J. Gen. Physiol. (2011)

Results from binding site models demonstrating the effect of an external field, in the form of an ion coordination number constraint, on K+/Na+ selectivity. Calculations were performed using the AMOEBA polarizable force field (Bostick and Brooks, 2010). (A) ΔΔG versus the number of included molecules, NI, in gas-phase clusters around K+ and Na+ in the absence of a constraint on coordination. As NI increases, the observed selectivity approaches values expected for bulk liquids (for water, ΔΔG ≈ 0; for formamide/NMA, ΔΔG < 0). Note that the number of included molecules, NI, is not necessarily equal to the number of coordinating molecules, NC, because of the absence of a coordination constraint. (B) ΔΔG versus the number of molecules, NC, directly coordinating K+ and Na+. In agreement with quantum mechanical calculations (Varma and Rempe, 2007, 2008), ΔΔG is larger in the water-based models (blue) than in the carbonyl-based models (black and red). Because of the presence of an external field (half-harmonic confinement) that imposes a specific coordination number, K+ selectivity is observed for seven or more ligands. In the models that coordinate K+ or Na+ with carbonyl ligands, K+ selectivity is determined by the external field rather than the ligand identity (NMA, formamide, and water) because the binding site models are Na+ selective in the absence of the constraint on coordination number, NC. (C) Contributions from specified individual components of the selectivity free energy (Eq. 2) in models composed of eight formamide molecules: ligand–ligand interactions,  ion–ligand interactions,  intramolecular interactions,  and entropy  In the case considered here, the contribution from the external field,  is negligible. In the absence of the field (left), the components yield net Na+ selectivity (ΔΔG < 0). When a field enforces eightfold coordination, the distribution of these individual components changes, producing net K+ selectivity (ΔΔG > 0). Thus, the redistribution of the individual components, and therefore the net K+ selectivity, is an effect of the applied external field.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3105521&req=5

fig4: Results from binding site models demonstrating the effect of an external field, in the form of an ion coordination number constraint, on K+/Na+ selectivity. Calculations were performed using the AMOEBA polarizable force field (Bostick and Brooks, 2010). (A) ΔΔG versus the number of included molecules, NI, in gas-phase clusters around K+ and Na+ in the absence of a constraint on coordination. As NI increases, the observed selectivity approaches values expected for bulk liquids (for water, ΔΔG ≈ 0; for formamide/NMA, ΔΔG < 0). Note that the number of included molecules, NI, is not necessarily equal to the number of coordinating molecules, NC, because of the absence of a coordination constraint. (B) ΔΔG versus the number of molecules, NC, directly coordinating K+ and Na+. In agreement with quantum mechanical calculations (Varma and Rempe, 2007, 2008), ΔΔG is larger in the water-based models (blue) than in the carbonyl-based models (black and red). Because of the presence of an external field (half-harmonic confinement) that imposes a specific coordination number, K+ selectivity is observed for seven or more ligands. In the models that coordinate K+ or Na+ with carbonyl ligands, K+ selectivity is determined by the external field rather than the ligand identity (NMA, formamide, and water) because the binding site models are Na+ selective in the absence of the constraint on coordination number, NC. (C) Contributions from specified individual components of the selectivity free energy (Eq. 2) in models composed of eight formamide molecules: ligand–ligand interactions, ion–ligand interactions, intramolecular interactions, and entropy In the case considered here, the contribution from the external field, is negligible. In the absence of the field (left), the components yield net Na+ selectivity (ΔΔG < 0). When a field enforces eightfold coordination, the distribution of these individual components changes, producing net K+ selectivity (ΔΔG > 0). Thus, the redistribution of the individual components, and therefore the net K+ selectivity, is an effect of the applied external field.
Mentions: Simulations of binding site models illustrate the consequences of constraints on coordination (Fig. 4). Coordination by five or six carbonyl oxygen atoms typically provides the weak selectivity observed in bulk liquids (Fig. 2), whereas strong K+ selectivity is associated with seven and eight coordinate complexes that resemble K+ channel architectures (Figs. 1 A and 4 B). In the absence of external forces imposing over-coordination, carbonyl ligands naturally assume a lower coordination number around each ion and K+/Na+ selectivity is lost (Fig. 4 A). Quantum mechanical studies of a model binding site composed of diglycine molecules show the same trends with Na+ binding (Varma and Rempe, 2007). These results support the argument that an environment that achieves high coordination numbers results in K+/Na+ selectivity, whereas an environment that permits relaxed coordination numbers produces lower selectivity. Note that this does not suggest that selectivity, in general, is solely controlled by coordination number: other types of constraints on an ion-bound complex can also play a role in selectivity, and ligand chemistry remains an important modulatory factor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological, Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, USA.

ABSTRACT

The advent of atomic resolution structures of ion-selective channels made possible the transition from black box models to molecular descriptions for considering the design principles underlying selectivity in a flexible selectivity filter. Simple theoretical models applied to interpret the complex behaviors observed in whole molecule experiments and molecular simulations led to suggestions that ligand type is of primary importance in determining selectivity. As discussed in this Perspective, this view is incomplete. Models that focus on chemical forces as a primary design principle do not explain why carbonyl ligands produce K+ selectivity in eightfold K+ channel&ndash;binding sites, but yield Na+ selectivity in liquid analogues (Fig. 2). Additionally, these models have not explained why chemically identical binding sites in the strongly selective KcsA channel show significantly different selectivities in simulations of whole channels. The same question applies to NaK channels, which lack selectivity despite sharing two chemically identical binding sites with strongly selective K+ channels. We are left with the conclusion that ion selectivity requires consideration of both ligand characteristics and the forces influencing binding site composition and structure.

Recent simulations support the view that interactions with the more distant environment of the membrane transport molecule can modify properties of the binding site and influence selective binding. In the case of K+ channels, restricted carbonyl motion or a decrease in their availability to the protein environment can drive up ion coordination numbers in the selectivity filter, leading to K+ selectivity. A snug fit as in valinomycin can be enforced by an environment that stabilizes intra-molecular hydrogen bonding, achieving selectivity without over-coordination through a constraint on cavity size. The importance of environmental controls on binding sites has since been recognized in several recent works (see, for example, Fowler et al., 2008; Miloshevsky and Jordan, 2008; Vora et al., 2008; Dixit et al., 2009; Dudev and Lim, 2009; Yu and Roux, 2009; Yu et al., 2009, 2010b; Roux, 2010; Rogers and Rempe, 2011). This Perspective provides a foundation necessary for understanding the more complex behavior of selective ion transport through membranes.

This Perspectives series includes articles by Andersen, Alam and Jiang, Nimigean and Allen, Roux et al., and Dixit and Asthagiri.

Show MeSH
Related in: MedlinePlus