Modeling the Hidden Pathways of IKs Channel Activation

Fedida, David

doi:10.1016/j.bpj.2018.05.020

Cited by 3 publications

(2 citation statements)

References 17 publications

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“…Owing to its proximity to the GCMC region, the 1D-GCAP simulations were repeated for the δ protonated His278. GCMC results can be dependent on the tautomer and rotamer of histidine used in a simulation, 51 and these results are discussed in the Supporting Information, Figure S.6 .…”

Section: Methodsmentioning

confidence: 99%

Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations

Macdonald

Cave-Ayland

Ross

et al. 2018

J. Chem. Theory Comput.

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Computational methods to calculate ligand binding affinities are increasing in popularity, due to improvements in simulation algorithms, computational resources, and easy-to-use software. However, issues can arise in relative ligand binding free energy simulations if the ligands considered have different active site water networks, as simulations are typically performed with a predetermined number of water molecules (fixed N ensembles) in preassigned locations. If an alchemical perturbation is attempted where the change should result in a different active site water network, the water molecules may not be able to adapt appropriately within the time scales of the simulations—particularly if the active site is occluded. By combining the grand canonical ensemble (μVT) to sample active site water molecules, with conventional alchemical free energy methods, the water network is able to dynamically adapt to the changing ligand. We refer to this approach as grand canonical alchemical perturbation (GCAP). In this work we demonstrate GCAP for two systems; Scytalone Dehydratase (SD) and Adenosine A2A receptor. For both systems, GCAP is shown to perform well at reproducing experimental binding affinities. Calculating the relative binding affinities with a naïve, conventional attempt to solvate the active site illustrates how poor results can be if proper consideration of water molecules in occluded pockets is neglected. GCAP results are shown to be consistent with time-consuming double decoupling simulations. In addition, by obtaining the free energy surface for ligand perturbations, as a function of both the free energy coupling parameter and water chemical potential, it is possible to directly deconvolute the binding energetics in terms of protein–ligand direct interactions and protein binding site hydration.

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Section: Methodsmentioning

confidence: 99%

Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations

Macdonald

Cave-Ayland

Ross

et al. 2018

J. Chem. Theory Comput.

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“…The exact stoichiometry of assembled physiologically relevant channels remains unknown as some lines of evidence point toward 4:2 ( Morin and Kobertz, 2008 ; Plant et al, 2014 ) while others including the cryo-EM structure of KCNQ1/KCNE3 (a paralog of KCNE1) supports the idea that a 4:4 stoichiometry ( Sun and MacKinnon, 2020 ). It is generally accepted that the ratio of KCNE1 to KCNQ1 subunits in I KS channels is flexible ( Murray et al, 2016 ; Fedida, 2018 ; Wang et al, 2020a ; Wang et al, 2020b ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological rescue of specific long QT variants of KCNQ1/KCNE1 channels

Zou

Sampson

et al. 2022

Front. Physiol.

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The congenital Long QT Syndrome (LQTS) is an inherited disorder in which cardiac ventricular repolarization is delayed and predisposes patients to cardiac arrhythmias and sudden cardiac death. LQT1 and LQT5 are LQTS variants caused by mutations in KCNQ1 or KCNE1 genes respectively. KCNQ1 and KCNE1 co-assemble to form critical IKS potassium channels. Beta-blockers are the standard of care for the treatment of LQT1, however, doing so based on mechanisms other than correcting the loss-of-function of K+ channels. ML277 and R-L3 are compounds that enhance IKS channels and slow channel deactivation in a manner that is dependent on the stoichiometry of KCNE1 subunits in the assembled channels. In this paper, we used expression of IKS channels in Chinese hamster ovary (CHO) cells and Xenopus oocytes to study the potential of these two drugs (ML277 and R-L3) for the rescue of LQT1 and LQT5 mutant channels. We focused on the LQT1 mutation KCNQ1-S546L, and two LQT5 mutations, KCNE1-L51H and KCNE1-G52R. We found ML277 and R-L3 potentiated homozygote LQTS mutations in the IKS complexes-KCNE1-G52R and KCNE1-L51H and in heterogeneous IKS channel complexes which mimic heterogeneous expression of mutations in patients. ML277 and R-L3 increased the mutant IKS current amplitude and slowed current deactivation, but not in wild type (WT) IKS. We obtained similar results in the LQT1 mutant (KCNQ1 S546L/KCNE1) with ML277 and R-L3. ML277 and R-L3 had a similar effect on the LQT1 and LQT5 mutants, however, ML277 was more effective than R-L3 in this modulation. Importantly we found that not all LQT5 mutants expressed with KCNQ1 resulted in channels that are potentiated by these drugs as the KCNE1 mutant D76N inhibited drug action when expressed with KCNQ1. Thus, our work shows that by directly studying the treatment of LQT1 and LQT5 mutations with ML277 and R-L3, we will understand the potential utility of these activators as options in specific LQTS therapeutics.

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Emerging methods to model cardiac ion channel and myocyte electrophysiology

Moreno

Silva

2023

Biophysics Reviews

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In the field of cardiac electrophysiology, modeling has played a central role for many decades. However, even though the effort is well-established, it has recently seen a rapid and sustained evolution in the complexity and predictive power of the models being created. In particular, new approaches to modeling have allowed the tracking of parallel and interconnected processes that span from the nanometers and femtoseconds that determine ion channel gating to the centimeters and minutes needed to describe an arrhythmia. The connection between scales has brought unprecedented insight into cardiac arrhythmia mechanisms and drug therapies. This review focuses on the generation of these models from first principles, generation of detailed models to describe ion channel kinetics, algorithms to create and numerically solve kinetic models, and new approaches toward data gathering that parameterize these models. While we focus on application of these models for cardiac arrhythmia, these concepts are widely applicable to model the physiology and pathophysiology of any excitable cell.

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Modeling the Hidden Pathways of IKs Channel Activation

Cited by 3 publications

References 17 publications

Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations

Ligand Binding Free Energies with Adaptive Water Networks: Two-Dimensional Grand Canonical Alchemical Perturbations

Pharmacological rescue of specific long QT variants of KCNQ1/KCNE1 channels

Emerging methods to model cardiac ion channel and myocyte electrophysiology

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