Building KCNQ1/KCNE1 Channel Models and Probing their Interactions by Molecular-Dynamics Simulations

Authors

Yu Xu, Virginia Commonwealth UniversityFollow
Yuhong Wang, Virginia Commonwealth UniversityFollow
Xuan-Yu Meng, Virginia Commonwealth University
Mei Zhang, Virginia Commonwealth UniversityFollow
Min Jiang, Virginia Commonwealth UniversityFollow
Meng Cui, Virginia Commonwealth UniversityFollow
Gea-Ny Tseng, Virginia Commonwealth UniversityFollow

Document Type

Article

Original Publication Date

2013

Journal/Book/Conference Title

Biophysical Journal

Volume

105

Issue

11

First Page

2461

DOI of Original Publication

10.1016/j.bpj.2013.09.058

Comments

Originally published at: http://dx.doi.org/10.1016/j.bpj.2013.09.058

Under an Elsevier user license.

Date of Submission

January 2015

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.

Rights

From The Biophysical Journal, Xu,Y., Wang, Y., Meng, XY et al., Building KCNQ1/KCNE1 Channel Models and Probing their Interactions by Molecular-Dynamics Simulations, Vol. 105, Page 2461. Copyright © 2013 Biophysical Society. Published by Elsevier Inc. Reprinted with permission.

Is Part Of

VCU Physiology and Biophysics Publications