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An entropic mechanism of generating selective ion binding in macromolecules.

Thomas M, Jayatilaka D, Corry B - PLoS Comput. Biol. (2013)

Bottom Line: Several mechanisms have been proposed to explain how ion channels and transporters distinguish between similar ions, a process crucial for maintaining proper cell function.Each operates in subtly different ways yet can produce markedly different influences on ion selectivity.Simple abstract-ligand models, as well as simple models based upon the ion binding sites in two amino acid transporters, show that limiting ligand fluctuations can create ion selectivity between Li(+), Na(+) and K(+) even when there is no strain associated with the molecular framework accommodating the different ions.

View Article: PubMed Central - PubMed

Affiliation: Research School of Biology, Australian National University, Canberra, Australia.

ABSTRACT
Several mechanisms have been proposed to explain how ion channels and transporters distinguish between similar ions, a process crucial for maintaining proper cell function. Of these, three can be broadly classed as mechanisms involving specific positional constraints on the ion coordinating ligands which arise through: a "rigid cavity", a 'strained cavity' and 'reduced ligand fluctuations'. Each operates in subtly different ways yet can produce markedly different influences on ion selectivity. Here we expand upon preliminary investigations into the reduced ligand fluctuation mechanism of ion selectivity by simulating how a series of model systems respond to a decrease in ligand thermal fluctuations while simultaneously maintaining optimal ion-ligand binding distances. Simple abstract-ligand models, as well as simple models based upon the ion binding sites in two amino acid transporters, show that limiting ligand fluctuations can create ion selectivity between Li(+), Na(+) and K(+) even when there is no strain associated with the molecular framework accommodating the different ions. Reducing the fluctuations in the position of the coordinating ligands contributes to selectivity toward the smaller of two ions as a consequence of entropic differences.

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The effect of reducing the fluctuations of the ligands in the amino acid transporter model sites.(A) Na+ in the GltPh model sites Na1 and Na2 being morphed to K+ (orange and dark red) or Li+ (light green and dark green). (B) Na+ in the LeuT model sites Na1 and Na2 being morphed to K+ (solid orange and dotted dark red) and Li+ (dotted light green and solid dark green). (C) The same free energies as (A) plotted against RMS fluctuations. The grey area corresponds to the observed RMS fluctuations in full system simulations of GltPh conducted in other studies [12], [34]. (D) The same free energies as (B) plotted against RMS fluctuations. Negative values (blue region) indicate Na+ selectivity, positive values (red regions) indicates K+ or Li+ selectivity.
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pcbi-1002914-g006: The effect of reducing the fluctuations of the ligands in the amino acid transporter model sites.(A) Na+ in the GltPh model sites Na1 and Na2 being morphed to K+ (orange and dark red) or Li+ (light green and dark green). (B) Na+ in the LeuT model sites Na1 and Na2 being morphed to K+ (solid orange and dotted dark red) and Li+ (dotted light green and solid dark green). (C) The same free energies as (A) plotted against RMS fluctuations. The grey area corresponds to the observed RMS fluctuations in full system simulations of GltPh conducted in other studies [12], [34]. (D) The same free energies as (B) plotted against RMS fluctuations. Negative values (blue region) indicate Na+ selectivity, positive values (red regions) indicates K+ or Li+ selectivity.

Mentions: As the amount of allowed fluctuation in the ligands of the amino acid transporter models are reduced ( increased), the change in the free energy of the exchange reaction between two ions () behaves in a very similar manner to the abstract models; the decrease in fluctuation contributes selectivity to the smaller of the two competing ions (Fig. 6). If we recall that the most of the oxygen atoms in GltPh and LeuT displayed RMS fluctuations greater than 0.7 Å, we see from Fig. 6 C and D that there is little to no contribution toward ion selectivity in this region. However, this contribution becomes significant for RMS fluctuation values observed for the oxygen atoms at the ion binding sites (the grey regions in Fig. 6 C and D). In this model, the ligands are able to adopt a preferred ion-ligand distance, and at no energy cost (in contrast to the strained cavity mechanism), yet a degree of ion selectivity is still created by the reduction in ligand fluctuation. A decomposition of the free energy change in each of the sites into the enthalpic and entropic contributions clearly demonstrate that this effect is primarily a consequence of entropy differences (Fig. 7).


An entropic mechanism of generating selective ion binding in macromolecules.

Thomas M, Jayatilaka D, Corry B - PLoS Comput. Biol. (2013)

The effect of reducing the fluctuations of the ligands in the amino acid transporter model sites.(A) Na+ in the GltPh model sites Na1 and Na2 being morphed to K+ (orange and dark red) or Li+ (light green and dark green). (B) Na+ in the LeuT model sites Na1 and Na2 being morphed to K+ (solid orange and dotted dark red) and Li+ (dotted light green and solid dark green). (C) The same free energies as (A) plotted against RMS fluctuations. The grey area corresponds to the observed RMS fluctuations in full system simulations of GltPh conducted in other studies [12], [34]. (D) The same free energies as (B) plotted against RMS fluctuations. Negative values (blue region) indicate Na+ selectivity, positive values (red regions) indicates K+ or Li+ selectivity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585399&req=5

pcbi-1002914-g006: The effect of reducing the fluctuations of the ligands in the amino acid transporter model sites.(A) Na+ in the GltPh model sites Na1 and Na2 being morphed to K+ (orange and dark red) or Li+ (light green and dark green). (B) Na+ in the LeuT model sites Na1 and Na2 being morphed to K+ (solid orange and dotted dark red) and Li+ (dotted light green and solid dark green). (C) The same free energies as (A) plotted against RMS fluctuations. The grey area corresponds to the observed RMS fluctuations in full system simulations of GltPh conducted in other studies [12], [34]. (D) The same free energies as (B) plotted against RMS fluctuations. Negative values (blue region) indicate Na+ selectivity, positive values (red regions) indicates K+ or Li+ selectivity.
Mentions: As the amount of allowed fluctuation in the ligands of the amino acid transporter models are reduced ( increased), the change in the free energy of the exchange reaction between two ions () behaves in a very similar manner to the abstract models; the decrease in fluctuation contributes selectivity to the smaller of the two competing ions (Fig. 6). If we recall that the most of the oxygen atoms in GltPh and LeuT displayed RMS fluctuations greater than 0.7 Å, we see from Fig. 6 C and D that there is little to no contribution toward ion selectivity in this region. However, this contribution becomes significant for RMS fluctuation values observed for the oxygen atoms at the ion binding sites (the grey regions in Fig. 6 C and D). In this model, the ligands are able to adopt a preferred ion-ligand distance, and at no energy cost (in contrast to the strained cavity mechanism), yet a degree of ion selectivity is still created by the reduction in ligand fluctuation. A decomposition of the free energy change in each of the sites into the enthalpic and entropic contributions clearly demonstrate that this effect is primarily a consequence of entropy differences (Fig. 7).

Bottom Line: Several mechanisms have been proposed to explain how ion channels and transporters distinguish between similar ions, a process crucial for maintaining proper cell function.Each operates in subtly different ways yet can produce markedly different influences on ion selectivity.Simple abstract-ligand models, as well as simple models based upon the ion binding sites in two amino acid transporters, show that limiting ligand fluctuations can create ion selectivity between Li(+), Na(+) and K(+) even when there is no strain associated with the molecular framework accommodating the different ions.

View Article: PubMed Central - PubMed

Affiliation: Research School of Biology, Australian National University, Canberra, Australia.

ABSTRACT
Several mechanisms have been proposed to explain how ion channels and transporters distinguish between similar ions, a process crucial for maintaining proper cell function. Of these, three can be broadly classed as mechanisms involving specific positional constraints on the ion coordinating ligands which arise through: a "rigid cavity", a 'strained cavity' and 'reduced ligand fluctuations'. Each operates in subtly different ways yet can produce markedly different influences on ion selectivity. Here we expand upon preliminary investigations into the reduced ligand fluctuation mechanism of ion selectivity by simulating how a series of model systems respond to a decrease in ligand thermal fluctuations while simultaneously maintaining optimal ion-ligand binding distances. Simple abstract-ligand models, as well as simple models based upon the ion binding sites in two amino acid transporters, show that limiting ligand fluctuations can create ion selectivity between Li(+), Na(+) and K(+) even when there is no strain associated with the molecular framework accommodating the different ions. Reducing the fluctuations in the position of the coordinating ligands contributes to selectivity toward the smaller of two ions as a consequence of entropic differences.

Show MeSH
Related in: MedlinePlus