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

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

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
Experimental estimates of selectivity free energy,  for different organic solvents with respect to bulk liquid water (Cox and Parker, 1973; Marcus, 1983; Schmid et al., 2000; Yu et al., 2010a). For these estimates,  is the partial molar Gibbs free energy for ion X in the specified medium relative to an ideal standard state, so that ΔG vanishes when ion–medium interactions vanish.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3105521&req=5

fig2: Experimental estimates of selectivity free energy, for different organic solvents with respect to bulk liquid water (Cox and Parker, 1973; Marcus, 1983; Schmid et al., 2000; Yu et al., 2010a). For these estimates, is the partial molar Gibbs free energy for ion X in the specified medium relative to an ideal standard state, so that ΔG vanishes when ion–medium interactions vanish.

Mentions: In a bulk liquid setting, the experimental free energy differences are unambiguous. For example, Fig. 2 displays the selectivity free energy for a variety of organic solvents relative to water as determined from experiments. As noted previously (Varma and Rempe, 2007; Bostick and Brooks, 2009; Asthagiri et al., 2010), some solvents display positive (K+) selectivity and some display negative (Na+) selectivity. The organic solvents composed of molecular analogues of the protein backbone, formamide and N-methylacetamide (NMA), are particularly interesting. These coordinate K+/Na+ with carbonyl oxygen atoms and provide Na+ selectivity. Also providing Na+ selectivity are the liquids that coordinate these ions with hydroxyl oxygen atoms, including methanol, ethanol, and propanol.


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

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

Experimental estimates of selectivity free energy,  for different organic solvents with respect to bulk liquid water (Cox and Parker, 1973; Marcus, 1983; Schmid et al., 2000; Yu et al., 2010a). For these estimates,  is the partial molar Gibbs free energy for ion X in the specified medium relative to an ideal standard state, so that ΔG vanishes when ion–medium interactions vanish.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105521&req=5

fig2: Experimental estimates of selectivity free energy, for different organic solvents with respect to bulk liquid water (Cox and Parker, 1973; Marcus, 1983; Schmid et al., 2000; Yu et al., 2010a). For these estimates, is the partial molar Gibbs free energy for ion X in the specified medium relative to an ideal standard state, so that ΔG vanishes when ion–medium interactions vanish.
Mentions: In a bulk liquid setting, the experimental free energy differences are unambiguous. For example, Fig. 2 displays the selectivity free energy for a variety of organic solvents relative to water as determined from experiments. As noted previously (Varma and Rempe, 2007; Bostick and Brooks, 2009; Asthagiri et al., 2010), some solvents display positive (K+) selectivity and some display negative (Na+) selectivity. The organic solvents composed of molecular analogues of the protein backbone, formamide and N-methylacetamide (NMA), are particularly interesting. These coordinate K+/Na+ with carbonyl oxygen atoms and provide Na+ selectivity. Also providing Na+ selectivity are the liquids that coordinate these ions with hydroxyl oxygen atoms, including methanol, ethanol, and propanol.

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