An Entropic Mechanism of Generating Selective Ion Binding in Macromolecules

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. Author Summary: Differentiating between Na+ and K+ ions is important for many cellular processes, such as nerve conduction and the regulation of membrane potentials. Different biological molecules utilise different methods to discriminate between ions. In this work, the reduced ligand fluctuation mechanism of ion selectivity is described. This entropy-driven mechanism is due to the limited thermal fluctuations of the atoms in some macromolecular ion binding sites. The elucidation of this mechanism offers a more complete picture of the ways in which the fundamental process of ion selectivity can be achieved.