The Role of Architectural and Structural Forces in Ion Selectivity

Abstract

A novel theoretical framework is presented to clarify the role of architectural and structural forces in ion selectivity by expressing the relative free energy of bound ions in terms of a reduced local system coupled to a potential of mean force (PMF) representing the influence of the surrounding environment. The PMF is separated into two contributions. The first includes all the harsh forces keeping the ion and the coordinating ligands confined to a small microscopic region, but do not prevent the ligands from adapting to ions of different radii. The second regroups all the remaining forces that serve to dictate a precise geometry of the coordinating ligands best adapted to a given ion. In the limit where the precise geometric forces are dominant, the binding site is almost rigid and ion selectivity is controlled by the ion-ligand interactions according to the classic “snug-fit” mechanism of host-guest chemistry. In the limit where the precise geometric forces are negligible, the ion and ligands behave as a self-organized “confined droplet” that is free to fluctuate and adapt to a smaller ion. But selectivity can also occur under such conditions. In the small and crowded volume, ion selectivity is determined by the ion-ligand and ligand-ligand interactions and is controlled by the number and the chemical type of ion-coordinating ligands. The theoretical framework is used to analyze K+ binding sites in the KcsA channel and Na+ binding sites in the LeuT transporter.