Structural modeling of hERG channel: Drug interactions using Rosetta

Human Ether-a-go-go-Related Gene (hERG) encodes a potassium-selective voltage-gated ion channel essential for normal electrical activity in the heart but is also a major drug anti-target. Genetic hERG mutations and blockage of the channel pore by drugs can cause long QT syndrome (LQTS), which predisposes individuals to potentially deadly arrhythmias.  However, not all hERG blocking drugs are pro-arrhythmic, and their differential affinities to discrete channel conformational states have been suggested to contribute to arrhythmogenicity. We used Rosetta electron density refinement and homology modeling to build structural models of open-state hERG channel wild-type (WT) and mutant variants (Y652A, F656A, and Y652A/F656A), and a closed state WT channel based on cryo-electron microscopy structures of hERG and EAG1 channels. These models were used as protein targets for molecular docking of charged and neutral forms of amiodarone, nifekalant, dofetilide, d/l-sotalol, flecainide, and moxiflo..., Rosetta modeling of hERG in open and closed states: We used the Rosetta structural modeling software (Bender et al., 2016;Leman et al., 2020) and the CryoEM structures of a putatively open-state hERG (PDB ID: 5VA2) (Wang and MacKinnon, 2017) and a closed-state EAG1 (PDB ID: 5K7L) (Whicher and MacKinnon, 2016) as templates (Figure 1). Each structure was passed through the cryo-EM density refinement protocol in Rosetta (Wang et al., 2016) (Supplement Script 1). The lowest scoring density-refitted models were then used in RosettaCM (Song et al., 2013) to model the channel’s unresolved residues and atoms in the extracellular region (Supplement Script 2). We generated 10,000 structural models of both open and closed state and selected the top 1,000 from each for RosettaLigand modeling of hERG interaction with drugs (described below). The lowest energy structures were visually inspected before being selected for the docking study. UCSF Chimera’s rotamer tool was used to make the F656A, Y652A,..., UCSF Chimera: https://www.cgl.ucsf.edu/chimera/
Reference
Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E. (2004). UCSF Chimera--a visualization system for exploratory research and analysis. J Comput Chem 25, 1605-1612., # Structural Modeling of hERG Channel – Drug Interactions Using Rosetta

## Description of the data and file structure

This README file was generated on 2023-12-20 by Vladimir Yarov-Yarovoy and Igor Vorobyov.

 
GENERAL INFORMATION

1\. Title of Dataset: Structural modeling of hERG channel: Drug interactions using Rosetta

2\. Author Information

            A. Principal Investigator Contact Information

             Name: Vladimir Yarov-Yarovoy         

             Institution: University of California, Davis

             Address: Davis, CA USA

             Email:

 

            B. Co-Principal Investigator Contact Information

               Name: Igor Vorobyov

                         Institution: University of California, Davis

                         Address: Davis, CA USA

                         Email:

3\. Date of data collection (single date, range, approximate date): 2018-2022

4\. Geographic location of data collection: Davis, CA USA

5\. Information about fun...