Referenced in: none

Automatically associated channels: Kv7.1 , Slo1 , TASK1

Title: Building KCNQ1/KCNE1 channel models and probing their interactions by molecular-dynamics simulations.

Authors: Yu Xu, Yuhong Wang, Xuan-Yu Meng, Mei Zhang, Min Jiang, Meng Cui, Gea-Ny Tseng

Journal, date & volume: Biophys. J., 2013 Dec 3 , 105, 2461-73

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24314077

Abstract
The slow delayed rectifier (I(KS)) channel is composed of KCNQ1 (pore-forming) and KCNE1 (auxiliary) subunits, and functions as a repolarization reserve in the human heart. Design of I(KS)-targeting anti-arrhythmic drugs requires detailed three-dimensional structures of the KCNQ1/KCNE1 complex, a task made possible by Kv channel crystal structures (templates for KCNQ1 homology-modeling) and KCNE1 NMR structures. Our goal was to build KCNQ1/KCNE1 models and extract mechanistic information about their interactions by molecular-dynamics simulations in an explicit lipid/solvent environment. We validated our models by confirming two sets of model-generated predictions that were independent from the spatial restraints used in model-building. Detailed analysis of the molecular-dynamics trajectories revealed previously unrecognized KCNQ1/KCNE1 interactions, whose relevance in I(KS) channel function was confirmed by voltage-clamp experiments. Our models and analyses suggest three mechanisms by which KCNE1 slows KCNQ1 activation: by promoting S6 bending at the Pro hinge that closes the activation gate; by promoting a downward movement of gating charge on S4; and by establishing a network of electrostatic interactions with KCNQ1 on the extracellular surface that stabilizes the channel in a pre-open activated state. Our data also suggest how KCNE1 may affect the KCNQ1 pore conductance.