Ion channels and ion selectivity

Abstract

Specific macromolecular transport systems, ion channels and pumps, provide the pathways to facilitate and control the passage of ions across the lipid membrane. Ion channels provide energetically favourable passage for ions to diffuse rapidly and passively according to their electrochemical potential. Selective ion channels are essential for the excitability of biological membranes: the action potential is a transient phenomenon that reflects the rapid opening and closing of voltage-dependent Na⁺-selective and K⁺-selective channels. One of the most critical functional aspects of K⁺ channels is their ability to remain highly selective for K⁺ over Na⁺ while allowing high-throughput ion conduction at a rate close to the diffusion limit. Permeation through the K⁺ channel selectivity filter is believed to proceed as a 'knockon' mechanism, in which 2-3 K⁺ ions interspersed by water molecules move in a single file. Permeation through the comparatively wider and less selective Na⁺ channels also proceeds via a loosely coupled knockon mechanism, although the ions do not need to be fully dehydrated. While simple structural concepts are often invoked to rationalize the mechanism of ion selectivity, a deeper analysis shows that subtle effects play an important role in these flexible dynamical structures.

Keywords: free energy; hydration; molecular dynamics; solvation.

Figure 1

Overall structure of voltage-gated K⁺ (Kv) and Na⁺ (Nav) channels. The Kv channel (a) is the mammalian Kv1.2/Kv2.1 chimera structure protein data base (PDB) entry: 2R9R (Long et al., 2007). The Nav channel (b) is the bacterial NavAb structure PDB entry 3RVY (Payandeh et al., 2011). At the top is a view of the tetrameric channels seen from the extracellular side. In the middle is a side view of the channels. At the bottom is a close-up view of the selectivity filter. In the Kv channel (a), the narrow selectivity filter of K⁺ channels comprises 5 distinct binding sites (S₀ to S₄) where the permeating K⁺ ions are coordinated by backbone carbonyl oxygens. In the Nav channel (b), the selectivity filter is relatively wide, allowing the passage of partially hydrated ions. A few binding sites have also been identified (Payandeh et al., 2011).

Figure 2

Schematic illustration of fundamental concepts in thermodynamic ion binding selectivity. In (a), the K⁺ and Na⁺ ions are pictured in bulk solution with their first hydration shell. The difference in hydration free energy ΔG_bulk between these two cations is ~18 kcal/mol. Binding to a rigid host (b) with a cavity size matching precisely a K⁺ ion (left) does not provide a favorable environment for the smaller Na⁺ (right). In this case, selectivity arises from the poor coordination interaction free energy ΔG_int between the ion and its rigid host. This is the classical snug-fit mechanism of host-guest chemistry. However, selectivity may also be achieved by a flexible host (c) that is able to deform and adapt to both K⁺ and Na⁺ ion if there is a sufficient build-up of strain energy ΔG_strain (illustrated as a deformation of the blue molecular scaffolding). Reproduced with permission from (Noskov and Roux, 2007).