Computer Simulations of Voltage-Gated Cation Channels

Abstract

The relentless growth in computational power has seen increasing applications of molecular dynamics (MD) simulation to the study of membrane proteins in realistic membrane environments, which include explicit membrane lipids, water and ions. The concomitant increasing availability of membrane protein structures for ion channels, and transporters -- to name just two examples -- has stimulated many of these MD studies. In the case of voltage-gated cation channels (VGCCs) recent computational works have focused on ion-conduction and gating mechanisms, along with their regulation by agonist/antagonist ligands. The information garnered from these computational studies is largely inaccessible to experiment and is crucial for understanding the interplay between the structure and function as well as providing new directions for experiments. This article highlights recent advances in probing the structure and function of potassium channels and offers a perspective on the challenges likely to arise in making analogous progress in characterizing sodium channels.

Sodium channel selectivity and conduction: Prokaryotes have devised their own molecular strategy

“…The pore radius at the constriction is still considerably wider than that for K channels. This finding is in keeping with previous data on the ion hydration in the pore ( Corry and Thomas, 2012 ; Treptow and Klein, 2012 ), which suggest that the permeant cation (either Na + or K + ) is able to maintain partial hydration and could possibly be accommodated by either WT or E/D mutant. The pore radius decreased slightly with the E177D mutation despite the shorter side chain introduced.…”

Concentration-Dependent Binding of Small Ligands to Multiple Saturable Sites in Membrane Proteins

“…On the other hand, the unfavorable or absent interactions at the central cavity and next the selectivity filter of Kv1.2 contrasts with sevoflurane binding at analogous regions of NaChBac 11 due major structural differences between Na + and K + channels. Specifically, the central cavity of potassium channels misses open-fenestrations of the sodium relatives 29 and K + -selective filters are sharply distinct from Na + -selective ones 30 . Because sevoflurane induces potentiation rather than blocking of Kv1.2, we read the negligible or absent density of the ligand at the central-cavity of the pore in Fig.…”

Conduction in a Biological Sodium Selective Channel

“…4,6 The latter involves a single file of ion and water molecules, which moves coherently when nudged by a third ion external to the SF thus defining a process involving a bistable (up−down) throughput cycle of two SFbound K + ions.…”