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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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Dependence of K+/Na+ selectivity on ligand composition in eight-ligand binding site models where ligand distances are generically confined to be within a 3.5-Å radius of the central ion. (A) The conventional field strength trend observed by Eisenman is illustrated by the dependence of selectivity, ΔΔG, on the dipole moment of linear ligands. Results were taken from binding site models described previously (red triangles, Noskov et al., 2004; black triangles, Thomas et al., 2007; circles were calculated with standard [black] or modified [red] CHARMM parameters, Bostick et al., 2009). Filled circles show results from a half-harmonic boundary restraint, and open circles show the corresponding Lennard-Jones restraint. The conventional field strength trend (dashed line) is independent of these different restraints. (B) Dependence of K+/Na+ selectivity, ΔΔG, on incremental replacement of carbonyl-like dipolar groups with water molecules. In contrast to the trend in A, recent work predicted a systematic loss of selectivity for each water molecule that replaces a carbonyl group (∼1.8 kcal/mol per water using the CHARMM force field) (Noskov and Roux, 2006, 2007). The red line illustrates this trend toward Na+ selectivity, which supports the revised field strength model. Data from subsequent calculations (Bostick et al., 2009), using the same force field and either a Lennard-Jones (LJ, black solid lines/circles) or a half-harmonic (black dashed lines and open circles) confining potential, do not eliminate the K+ selectivity.
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fig3: Dependence of K+/Na+ selectivity on ligand composition in eight-ligand binding site models where ligand distances are generically confined to be within a 3.5-Å radius of the central ion. (A) The conventional field strength trend observed by Eisenman is illustrated by the dependence of selectivity, ΔΔG, on the dipole moment of linear ligands. Results were taken from binding site models described previously (red triangles, Noskov et al., 2004; black triangles, Thomas et al., 2007; circles were calculated with standard [black] or modified [red] CHARMM parameters, Bostick et al., 2009). Filled circles show results from a half-harmonic boundary restraint, and open circles show the corresponding Lennard-Jones restraint. The conventional field strength trend (dashed line) is independent of these different restraints. (B) Dependence of K+/Na+ selectivity, ΔΔG, on incremental replacement of carbonyl-like dipolar groups with water molecules. In contrast to the trend in A, recent work predicted a systematic loss of selectivity for each water molecule that replaces a carbonyl group (∼1.8 kcal/mol per water using the CHARMM force field) (Noskov and Roux, 2006, 2007). The red line illustrates this trend toward Na+ selectivity, which supports the revised field strength model. Data from subsequent calculations (Bostick et al., 2009), using the same force field and either a Lennard-Jones (LJ, black solid lines/circles) or a half-harmonic (black dashed lines and open circles) confining potential, do not eliminate the K+ selectivity.

Mentions: If this conventional ligand field strength model is applied to a K+/Na+-selective binding site, then decreasing the field strength of the ligand should increase selectivity for the larger K+ ion. Quantum mechanical calculations confirmed this trend for a hypothetical ion–ligand system in which substitution of ion-coordinating formamide by water (a carbonyl-to-water substitution) increases K+/Na+ selectivity (Varma and Rempe, 2007). The same behavior also occurred upon varying the ligand field strength in simulations (Fig. 3 A) of a simplified binding site of eight nonpolarizable linear ligands confined within a sphere of radius 3.5 Å around a central ion (Noskov et al., 2004; Thomas et al., 2007; Bostick et al., 2009).


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

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

Dependence of K+/Na+ selectivity on ligand composition in eight-ligand binding site models where ligand distances are generically confined to be within a 3.5-Å radius of the central ion. (A) The conventional field strength trend observed by Eisenman is illustrated by the dependence of selectivity, ΔΔG, on the dipole moment of linear ligands. Results were taken from binding site models described previously (red triangles, Noskov et al., 2004; black triangles, Thomas et al., 2007; circles were calculated with standard [black] or modified [red] CHARMM parameters, Bostick et al., 2009). Filled circles show results from a half-harmonic boundary restraint, and open circles show the corresponding Lennard-Jones restraint. The conventional field strength trend (dashed line) is independent of these different restraints. (B) Dependence of K+/Na+ selectivity, ΔΔG, on incremental replacement of carbonyl-like dipolar groups with water molecules. In contrast to the trend in A, recent work predicted a systematic loss of selectivity for each water molecule that replaces a carbonyl group (∼1.8 kcal/mol per water using the CHARMM force field) (Noskov and Roux, 2006, 2007). The red line illustrates this trend toward Na+ selectivity, which supports the revised field strength model. Data from subsequent calculations (Bostick et al., 2009), using the same force field and either a Lennard-Jones (LJ, black solid lines/circles) or a half-harmonic (black dashed lines and open circles) confining potential, do not eliminate the K+ selectivity.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105521&req=5

fig3: Dependence of K+/Na+ selectivity on ligand composition in eight-ligand binding site models where ligand distances are generically confined to be within a 3.5-Å radius of the central ion. (A) The conventional field strength trend observed by Eisenman is illustrated by the dependence of selectivity, ΔΔG, on the dipole moment of linear ligands. Results were taken from binding site models described previously (red triangles, Noskov et al., 2004; black triangles, Thomas et al., 2007; circles were calculated with standard [black] or modified [red] CHARMM parameters, Bostick et al., 2009). Filled circles show results from a half-harmonic boundary restraint, and open circles show the corresponding Lennard-Jones restraint. The conventional field strength trend (dashed line) is independent of these different restraints. (B) Dependence of K+/Na+ selectivity, ΔΔG, on incremental replacement of carbonyl-like dipolar groups with water molecules. In contrast to the trend in A, recent work predicted a systematic loss of selectivity for each water molecule that replaces a carbonyl group (∼1.8 kcal/mol per water using the CHARMM force field) (Noskov and Roux, 2006, 2007). The red line illustrates this trend toward Na+ selectivity, which supports the revised field strength model. Data from subsequent calculations (Bostick et al., 2009), using the same force field and either a Lennard-Jones (LJ, black solid lines/circles) or a half-harmonic (black dashed lines and open circles) confining potential, do not eliminate the K+ selectivity.
Mentions: If this conventional ligand field strength model is applied to a K+/Na+-selective binding site, then decreasing the field strength of the ligand should increase selectivity for the larger K+ ion. Quantum mechanical calculations confirmed this trend for a hypothetical ion–ligand system in which substitution of ion-coordinating formamide by water (a carbonyl-to-water substitution) increases K+/Na+ selectivity (Varma and Rempe, 2007). The same behavior also occurred upon varying the ligand field strength in simulations (Fig. 3 A) of a simplified binding site of eight nonpolarizable linear ligands confined within a sphere of radius 3.5 Å around a central ion (Noskov et al., 2004; Thomas et al., 2007; Bostick et al., 2009).

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–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