Abstract
The voltage-gated KCNQ1 potassium ion channel interacts with the type I transmembrane protein minK (KCNE1) to generate the slow delayed rectifier (IKs) current in the heart. Mutations in these transmembrane proteins have been linked with several heart-related issues, including long QT syndromes (LQTS), congenital atrial fibrillation, and short QT syndrome. Off-target interactions of several drugs with that of KCNQ1/KCNE1 ion channel complex have been known to cause fatal cardiac irregularities. Thus, KCNQ1/KCNE1 remains an important avenue for drug-design and discovery research. In this work, we present the structural and mechanistic details of potassium ion permeation through an open KCNQ1 structural model using the combined molecular dynamics and steered molecular dynamics simulations. We discuss the processes and key residues involved in the permeation of a potassium ion through the KCNQ1 ion channel, and how the ion permeation is affected by (i) the KCNQ1-KCNE1 interactions and (ii) the binding of chromanol 293B ligand and its derivatives into the complex. The results reveal that interactions between KCNQ1 with KCNE1 causes a pore constriction in the former, which in-turn forms small energetic barriers in the ion-permeation pathway. These findings correlate with the previous experimental reports that interactions of KCNE1 dramatically slows the activation of KCNQ1. Upon ligand-binding onto the complex, the energy-barriers along ion permeation path are more pronounced, as expected, therefore, requiring higher force in our steered-MD simulations. Nevertheless, pulling the ion when a weak blocker is bound to the channel does not necessitate high force in SMD. This indicates that our SMD simulations have been able to discern between strong and week blockers and reveal their influence on potassium ion permeation. The findings presented here will have some implications in understanding the potential off-target interactions of the drugs with the KCNQ1/KCNE1 channel that lead to cardiotoxic effects.
Highlights
The cardiac KCNQ1 is a voltage-gated potassium ion channel that is expressed in different tissues throughout the human body, including heart, brain, epithelia and smooth muscles [1]
We described the effects of KNCQ1-KCNE1 interactions and the small-molecule binding on the ion permeation mechanisms through the KCNQ1 channel, using atomistic and steered Molecular Dynamics (MD) simulations
The 3D structures of the open-state of the unbound-KCNQ1 and the KCNQ1/KCNE1 complex were initially equilibrated using long-scale MD simulations, which revealed that the complex form was more stable than that of the unbound-KCNQ1 channel
Summary
The cardiac KCNQ1 is a voltage-gated potassium ion channel that is expressed in different tissues throughout the human body, including heart, brain, epithelia and smooth muscles [1]. The KCNQ1 channel complexes with its beta-subunit, the transmembrane KCNE1 (minK) protein to constitute the slow component of the delayed rectifier current (IKS) [2]. This is mainly facilitated by allowing selective permeation of the potassium ions from the intracellular membrane to the extracellular environment, through the KCNQ1 channel [3,4]. The maintenance of this normal ion flux gives the KCNQ1/KCNE1 ion channel its unique role in controlling the duration of the repolarization phase of the cardiac action potential. A list of all known LQTS1-associated single-point mutations in human KCNQ1 channel are provided in S1 Table
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