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 at-omistic 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 model-ing 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 Per-spective'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. Theoretical progress can be made by methodologies that are capable of predicting ion concentration profiles. Here, we apply the 3-D reference interaction site the special case of a charged solute immersed in a salt solution (Kloss and Kast, 2008), to a truncated fragment comprising the selectivity filter of the KcsA channel in the conducting conformation (Zhou et al., 2001). The 3-D RISM approach is an approximate equilibrium solvation theory that retains the molecular detail of the solvent and that is therefore in principle capable of ion size discrimination on the basis of molecular force fields. Although it has well-known shortcomings in its established form, such as the neglect of intramolecular solute flexibility, it …