Understanding the Dynamics of K2P Channels in Complex Lipid Bilayers

Abstract

Ion channels are proteins that reside in phospholipid bilayers and conduct ions through their trans-membrane pore. Studying the dynamics of interaction between the channel, phospholipids, water and ions is fundamental to understanding ion channel function. We are using a combination of molecular dynamics simulations and functional tools to gain insight into K2P (Two Pore-domain Potassium Channel) function. By initially observing wetting and dewetting transitions in the inner pore of TWIK-1 (K2P1) channels during MD simulations and by subsequently combining in silico and in vitro mutagenesis and electrophysiology, we have found a hydrophobic barrier deep within the inner pore of the TWIK-1 channel [1]. Our study suggests that this barrier contributes to the very low level of functional currents observed for TWIK-1 channels. We have also reviewed the computational, structural and functional evidence for hydrophobic gating in several ion channel families and propose that understanding the dynamic behavior of water and ions within the pore represents an increasingly important element in understanding the relationship between ion channel structure and function [2]. We are now examining the interaction between K2P channels and phospholipids in more detail. Using MD simulations, we find hot spots for K2P channel and lipid interactions. These findings suggest that lipids can play modulatory roles in K2P channel function.[1] Aryal P, Abd-Wahab F, Bucci G, Sansom MSP & Tucker SJ. A hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel. Nature Communications 5:4377 (2014) [http://dx.doi.org/10.1038/ncomms5377][2] Aryal P, Sansom MSP and Tucker SJ. Hydrophobic Gating in Ion Channels. Journal of Molecular Biology (2014) [http://dx.doi.org/10.1016/j.jmb.2014.07.030]