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.
Highlights
The ability of some biological molecules to discriminate between different ions is crucial for their function
A pore lined with carboxylate groups, for example, is likely to have different ion selectivity to a pore lined with carbonyl groups
Reducing the thermal fluctuation in the positions of the coordinating ligands affects the binding of Li+, Na+ and K+ differently and is able to contribute toward ion selectivity, even when there is no strain associated with the protein adapting to different ions
Summary
The ability of some biological molecules to discriminate between different ions is crucial for their function This differentiation is important, for example, in the generation (or regulation) of the action potential during cellular signalling, and the maintenance of an electrochemical gradient across the cell membrane [1]. It is generally agreed that selectivity depends on a difference in free energy relative to bulk water of one ion compared to the other at some position within the transit pathway (i.e. how well the loss of free energy from dehydration is recouped by coordination with the protein), there are several different proposals which attempt to explain how this difference in free energy occurs These proposals fall into three broad categories related to: 1. When the smaller ion is favoured because the binding site
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