Abstract
Ion channels assist and control the diffusion of ions through biological membranes. The conduction process depends on the structural characteristics of these nanopores, among which are the hydrophobicity and the afforded diameter of the conduction pathway. In this contribution, we use full atomistic free-energy molecular dynamics simulations to estimate the effect of such characteristics on the energetics of ion conduction through the activation gate of voltage-gated potassium (Kv) channels. We consider specifically the ionic translocation through three different permeation pathways, corresponding to the activation gate of an atomistic model of Shaker channels in closed and partially opened conformations, and that of the open conformation of the Kv1.2 channel. In agreement with experiments, we find that the region of Val(478) constitutes the main gate. The conduction is unfavorable through this gate when the constriction is smaller than an estimated threshold of 4.5-5.0 A, mainly due to incomplete coordination-hydration of the ion. Above this critical size, e.g., for the Kv1.2, the valine gate is wide enough to allow fully coordination of the ion and therefore its diffusion on a flat energy surface. Similar to other ion channels, Kv channels appear therefore to regulate diffusion by constricting hydrophobic regions of the permeation pathway.