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A Comprehensive Dynamic Model for KCNQ1/KCNE1 Ion Channel: Structural & Functional Studies Open Access


Other title
cardiac ion channel
modeling proteins
Type of item
Degree grantor
University of Alberta
Author or creator
Jalily Hasani, Horia
Supervisor and department
El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
Barakat, Khaled (Faculty of Pharmacy and Pharmaceutical Sciences)
Examining committee member and department
Siraki, Arno (Faculty of Pharmacy and Pharmaceutical Sciences)
Velázquez-Martínez, Carlos (Faculty of Pharmacy and Pharmaceutical Sciences)
El-Kadi, Ayman (Faculty of Pharmacy and Pharmaceutical Sciences)
Barakat, Khaled (Faculty of Pharmacy and Pharmaceutical Sciences)
Faculty of Pharmacy and Pharmaceutical Sciences
Pharmaceutical Sciences
Date accepted
Graduation date
2017-11:Fall 2017
Master of Science
Degree level
The voltage-gated KCNQ1/KCNE1 potassium ion channel plays a key role in maintaining the heart rhythm. An active channel generates the slow delayed rectifier (IKs) current in the heart. Both loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1 are linked to many heart-related diseases, including long QT syndromes, congenital atrial fibrillation, and short QT syndrome. On the other hand, the KCNQ1/KCNE1 channel is also found to be an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. This Thesis aims at understanding the structure and function of the KCNQ1/KCNE1 ion channel at the atomistic level. To accomplish this task, we used several state-of-the-art molecular modeling approaches to build a structural model for KCNQ1 protein. This model was tested against available experimental data, which confirmed its accuracy. Following that, we included the KCNE1 protein component using a data-driven protein-protein docking simulation. The association of the KCNE1 protein with KCNQ1 had a profound effect on the dynamics of the KCNQ1 channel. More importantly, further ion permeation studies revealed that KCNE1 directly affects the pore topology, which translated into a slight blockade in ion permeation. This is in an excellent agreement with the well-documented effects of KCNE1 on KCNQ1, that is KCNE1 slows the activation of the channel. To our knowledge, this Thesis represents the first study to highlight the effect of the KCNE1 protein on the structure of the KCNQ1 pore domain as well as on the ion permeation through the channel. Next, we docked a panel of compounds consisting of Chromanol 293B and its 8 derivatives within the KCNQ1/KCNE1 channel. The predicted docking scores for the tested small molecules correlated well with the experimental activity of the compounds. This indicated that our model was able to discriminate between blockers of differential activities. Furthermore, Steered Molecular Dynamic simulations were performed on the ligand-bound channel complexes. Through this study we were able to directly investigate the effect of the blockers on ion permeation. Such that strong blockers had a profound effect on the passage of potassium ions, which was evident from their binding mode and interactions with the binding site residues, force profiles as well as from the pore topology analysis. The weak blockers on the other hand, did not have direct interference with the normal passage of ions. The structure activity relationships of the ligands revealed the pharmacophoric features responsible for the degree of their effect on the channel and allowed us to get more insights into how small molecule blockers can affect the orientation of specific residues in the protein. Overall, the findings from this Thesis are important and revealed novel aspects of the KCNQ1/KCNE1 channel complex. We believe that this Thesis is a good starting point for further studies to investigate different drug scaffolds and different mechanisms by which they can affect ion permeation in KCNQ1/KCNE1 ion channels. We hope that this work can allow the identification of potential cadiotoxic drug molecules early in the drug development stages and, consequently, prevent the unfortunate consequences of designing a drug molecule with potential toxicity to the heart.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Jalily Hasani H, Barakat K. Protein-Protein Docking: Are We There Yet?, Methods and Algorithms for Molecular Docking-Based Drug Design and Discovery. Dastmalchi S, Hamzeh-Mivehroud M, Sokouti B, editors. IGI Global; 173-195 p. 2016Jalily Hasani H, Barakat K. Homology Modeling: an Overview of Fundamentals and Tools. Int Rev Model Simulations (IREMOS); Vol 10, No 2. 201.

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