Ion selectivity in channels and transporters

Abstract

A multitude of biological processes requires the participation of specific cations, such as H + , Na + , K + , Ca 2+ , and Mg 2+ . Many of these processes can take place only when proteins have the ability to discriminate between different ions with a very high fidelity. How this is possible is a fundamental question that has fascinated scientists for a long time. At the most fundamental level, it is anticipated that ion selectivity must result from a delicate balance of strong interactions. Yet, identifying and quantifying the key microscopic factors is difficult, as many of these cannot be directly measured by experiments. Theory and computations can contribute by providing a virtual route to complement the missing information. Because ion selectivity is often dominated by thermodynamic factors, detailed molecular dynamics (MD) free energy simulations become important tools. This was vividly illustrated early on with studies of ion solvation (Straatsma and Berendsen, 1988;Åqvist, 1990) and ion-selective systems (Lybrand et al., 1986;Grootenhuis and Kollman, 1989;Åqvist, 1992). These pioneering studies inspired our own efforts.In this Perspective, we aim to present our understanding of ion selectivity as it has evolved over approximately 15 years from studies based on various specific structures: gramicidin A channels (e.g.

Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel

“…This suggests that the scaffold behind the K + -selective NaK2K selectivity filter is less dynamic or more structurally homogenous than in nonselective NaK. These results are consistent with a role for structural stability in maintaining a four-site ion-selective filter and K + -selectivity, a phenomenon that has been extensively studied previously (30). They also suggest that the observed coupling between the gates is tuned by the dynamic state of the protein.…”

Catalysis of Na + permeation in the bacterial sodium channel Na V Ab

“…Evidently, as early in evolution as bacteria, two fundamentally different structures and mechanisms had arisen for conduction of Na + versus K + in ion channels. In contrast to the classic "snug" or "induced fit" models of ion permeation, it is becoming recognized that protein flexibility plays a role in selective ion transport (27,28). The mechanism uncovered in the present study highlights the interplay of channel dynamics and ion movement.…”

Outlines of the pore in open and closed conformations describe the gating mechanism of ASIC1

“…It is unexpected that a channel that may rely on pore size to select the passing ions is also one that exhibits major changes in the diameter of the selectivity filter during gating. The notion that the selectivity filter of ion channels undergoes some degree of rearrangements during gating is not entirely foreign; analysis of the atomic structure together with detailed molecular dynamics free energy simulations have changed the classical snug-fit mechanism to more flexible binding sites influenced by local energetics (recently reviewed by Roux et al 19 ). However, in those instances, the proposed structural changes are slight compared with the whole assembly of ASIC1 selectivity filter shown by our results.…”