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


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.

SUBMITTER: Xu Y 

PROVIDER: S-EPMC3854563 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Xu Yu Y   Wang Yuhong Y   Meng Xuan-Yu XY   Zhang Mei M   Jiang Min M   Cui Meng M   Tseng Gea-Ny GN  

Biophysical journal 20131201 11


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 t  ...[more]

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