A minimalist model for ion partitioning and competition in a K+ channel selectivity filter

In the recent collection of articles in Perspectives on: Ion selectivity, several authors summarized the current state of knowledge on ion channel selectivity, predominated by experimental and theoretical approaches to understanding K+/Na+ discrimination of passive ion channels. Considerable insight has been gained by complementary analyses of crystal structures as well as by molecular simulations of models ranging from fully atomistic scenarios to simple “toys” that represent essential, localizable features of the overall phenomenon. On the theoretical side, much emphasis has been put on the thermodynamic aspect of selectivity, namely modeling and understanding the free energy change associated with K+/Na+ exchange in the selectivity filter of K+ channels. Numerous studies have convincingly shown (e.g., Dixit and Asthagiri, 2011; Roux et al., 2011; Varma et al., 2011) that thermodynamic selectivity results from a complex interplay between the chemical nature and number of coordinating ligands and the restricted inherent local atomic flexibility. However, both experimental (kinetic and structural analyses) and computational studies (multi-ion free energy surfaces) are directed toward understanding the ionic interplay and competition in the selectivity filter of K+ channels that give rise to complex kinetic features that are equally important signatures of ion selectivity (Alam and Jiang, 2011; Nimigean and Allen, 2011). As emphasized in the Perspective’s editorial (Andersen, 2011), further progress relies on converging thermodynamic (single ion) and kinetic (multi-ion) approaches into a unifying picture. The success of the latter depends strongly on the adequate treatment of physiological reference states. These are (in contrast to infinite dilution states, often implicitly assumed in free energy simulations) characterized by finite ion concentrations as needed for kinetic modeling, allowing for direct ion competition as a result of partitioning.