DOI: 10.5061/dryad.dfn2z357q
title: Structural modeling of hERG channel: Drug interactions using Rosetta

description: 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 moxifloxacin. We selected these drugs based on their
 different arrhythmogenic potentials and abilities to facilitate hERG
 current. Our docking studies and clustering provided atomistic structural
 insights into state-dependent drug–channel interactions l that play a key
 role in differentiating safe and harmful hERG blockers and can explain
 hERG channel facilitation through drug interactions with its open-state
 hydrophobic pockets.
description: <strong>Rosetta modeling of hERG in open and closed
 states:</strong> 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, and Y652A/F656A mutations
 based on the final wild-type open-state model.
 <strong>RosettaLigand modeling of hERG interaction with
 drugs: </strong>We obtained the molecular structures of each drug
 from the ZINC (Irwin and Shoichet, 2005) and PubChem (Kim et al., 2019)
 databases. OpenEye OMEGA (OpenEye Scientific Software) was used to
 generate conformers for the drugs (Hawkins et al., 2010). At a
 physiological pH 7.4, each drug exists in a dominant ionized (cationic or
 zwitterionic) form. However, because the drug receptor site in the pore
 lumen region is hydrophobic, this may shift the ionization equilibrium.
 This indicates that we need to study both ionized and neutral forms of
 each drug when analyzing its interactions with the hERG channel (Table 1)
 (Chatelain et al., 1986;Cross et al., 1990;Kodama et al., 1997;Hille,
 2001;Lemaire et al., 2011;Kazusa et al., 2014). Previous computational
 studies suggest that the cationic form of sotalol predominantly remains in
 an aqueous solution while the neutral form embeds into the membrane and
 interacts with the hERG channel (Yang et al., 2020;DeMarco et al., 2021),
 hence our inclusion of neutral drug docking results in the main
 text. To uniformly and efficiently sample the pore
 region, drugs were placed at 10 different initial locations spanning the
 top and bottom of the pore lumen region and the four fenestration regions.
 As part of the standard Rosetta docking protocol, we set the initial
 random perturbation to a translation distance less than 5Å and the
 sampling radius to 5Å (Supplement Script 3). The details of the
 RosettaLigand docking algorithm have been described previously (Meiler and
 Baker, 2006;Davis and Baker, 2009;Lemmon and Meiler, 2012;Combs et al.,
 2013;Bender et al., 2016;Leman et al., 2020). A total of 100,000 docking
 models were generated for each drug and each protein. The top 10,000 were
 selected based on the total_score of the protein-ligand complex and then
 ranked by ligand binding energy represented by the Rosetta
 interface_delta_X score term. The top 50 most favorable interface score
 models were visually analyzed using UCSF Chimera (Pettersen et al., 2004).
 The representative poses were further analyzed using the Protein-Ligand
 Interaction Profiler (PLIP) (Salentin et al., 2015) web service.
 Clustering analysis of docking results was done in R Studio by
 calculating a similarity matrix between all top 50 poses clustered based
 on a cutoff parameter and minimum cluster size parameter using equation
 (1) where z is drug center of mass (COM) position with respect to hERG SF
 Ca COM along the z-axis, l is length of the vector between end-point atoms
 of a drug molecule, and  is the polar angle of the drug end-point atoms’
 vector away from the z-axis (Supplement Table 1 and Supplement Scripts 4
 and 5). This ensures invariance to the rotation around
 the z-axis and, therefore, can account for the 4-fold symmetry of the hERG
 channel. Unique clusters were then identified using K-means optimization
 initialized using the lowest interface score structures from each cluster
 as the cluster centers. Percentage within hydrophobic
 pocket was calculated by proportion of poses of the top 50 models of each
 docking simulation with at least one atom positioned at or in the
 hydrophobic pocket of the hERG channel as visualized for each pose in
 Chimera (Figure 2). Percentage within closed pore of hERG channel
 calculated by counting number of poses of top 50 models for each docking
 simulation that are fully encapsulated within hERG channel pore or
 fenestration region (Figure 1D). <strong>IUPAC
 drug nomenclature:</strong> Amiodarone,
 (2-butyl-1-benzofuran-3-yl)-[4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl]methanone Nifekalant, 6-[(2-((2-hydroxyethyl)[3-(4-nitrophenyl)propyl]amino)ethyl)amino]-1,3-dimethylpyrimidine-2,4(1H,3H)-dione Flecainide, (RS)-N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide Moxifloxacin, 1-Cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Sotalol, (RS)-N-[4-[1-hydroxy-2-(propan-2  ylamino)ethyl]phenyl]methanesulfonamide Dofetilide, N-[4-(2-([2-(4-methane sulfonamidophenoxy)ethyl] (methyl)amino)ethyl)phenyl]methanesulfonamide
description: 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.
description: # 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 funding sources that supported the collection of the data: National
 Heart Lung and Blood Institute, Award: R01HL128537 National Heart Lung and
 Blood Institute, Award: U01HL126273 American Heart Association, Award:
 16PRE27260295 American Heart Association, Award: 19CDA34770101 National
 Heart Lung and Blood Institute, Award: R01HL152681 National Heart Lung and
 Blood Institute, Award: 5T32HL086350 SHARING/ACCESS INFORMATION 1\.
 Licenses/restrictions placed on the data: CC0 1.0 Universal (CC0 1.0)
 Public Domain 2\. Links to publications that cite or use the data: Aiyana
 M Emigh Cortez, Kevin R DeMarco, Kazuharu Furutani, Slava Bekker, Jon T
 Sack, Heike Wulff, Colleen E Clancy, Igor Vorobyov, Vladimir Yarov-Yarovoy
 (2023) Structural modeling of hERG channel: Drug interactions using
 Rosetta. Front Pharmacol 14:1244166. doi: 10.3389/fphar.2023.1244166. 3\.
 Links to other publicly accessible locations of the data: None 4\.
 Links/relationships to ancillary data sets: None 5\. Was data derived from
 another source? No             A. If yes, list source(s): NA 6\.
 Recommended citation for this dataset: Aiyana M Emigh Cortez, Kevin R
 DeMarco, Kazuharu Furutani, Slava Bekker, Jon T Sack, Heike Wulff, Colleen
 E Clancy, Igor Vorobyov, Vladimir Yarov-Yarovoy (2023) Data from:
 Structural modeling of hERG channel: Drug interactions using Rosetta.
 Front Pharmacol 14:1244166. doi: 10.3389/fphar.2023.1244166. Dryad Digital
 Repository. DATA &
 FILE OVERVIEW 1\. File List: A)    amiodarone.zip B)    closed-hERG-WT.pdb
 C)    d-sotalol.zip    D)    dofetilide.zip E)    flecainide.zip F)    
 l-sotalol.zip G)    moxifloxacin.zip H)    nifekalant.zip I)     
 open-hERG-WT.pdb J)     top-score-PDBs.zip 2\. Relationship between files,
 if important: None 3\. Additional related data collected that was not
 included in the current data package: None 4\. Are there multiple versions
 of the dataset? No             A. If yes, name of file(s) that was
 updated: NA                         i. Why was the file updated? NA
                         ii. When was the file updated? NA
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: amiodarone.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of amiodarone in neutral (0) or
 cationic (1) form docked to closed-state wild-type (WT), open-state WT,
 open-state Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-amiodarone1_top50_all.py – top 50 models of amiodarone in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-amiodarone1_top50_all.py - top 50 models of
 amiodarone in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-amiodarone0_top50_all.py – top 50
 models of amiodarone in neutral (0) form docked to WT hERG in a closed
 state.            open-hERG-WT-amiodarone0_top50_all.py – top 50 models of
 amiodarone in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-amiodarone0_top50_all.py – top 50 models
 of amiodarone in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-amiodarone1_top50_all.py – top 50 models of
 amiodarone in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-amiodarone1_top50_all.py – top 50 models of
 amiodarone in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-amiodarone1_top50_all.py – top 50 models
 of amiodarone in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-amiodarone0_top50_all.py – top 50 models of
 amiodarone in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-amiodarone0_top50_all.py - top 50 models
 of amiodarone in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.      2\. Each*.py file should be opened using UCSF
 Chimera software: 3\. Missing
 data codes: None 4\. Specialized formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: closed-hERG-WT.pdb 1\. Contains top scoring
 model of the wild-type (WT) hERG (human Ether-à-go-go-Related Gene)
 channel in a closed state in the PDB format.     2\. Each*.pdb file can be
 opened using UCSF Chimera or PyMol software:
 3\.
 Missing data codes: None 4\. Specialized formats or other abbreviations
 used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: d-sotalol.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of d-sotalol in neutral (0) or
 cationic (1) form docked to closed-state wild-type (WT), open-state WT,
 open-state Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-d-sotalol1_top50_all.py – top 50 models of d-sotalol in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-d-sotalol1_top50_all.py - top 50 models of d-sotalol
 in cationic (1) form docked to hERG double Y652A/F656A mutant in an open
 state.      closed-hERG-WT-d-sotalol0_top50_all.py – top 50 models of
 d-sotalol in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-d-sotalol0_top50_all.py – top 50 models of
 d-sotalol in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-d-sotalol0_top50_all.py – top 50 models
 of d-sotalol in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-d-sotalol1_top50_all.py – top 50 models of
 d-sotalol in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-d-sotalol1_top50_all.py – top 50 models of
 d-sotalol in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-d-sotalol1_top50_all.py – top 50 models
 of d-sotalol in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-d-sotalol0_top50_all.py – top 50 models of
 d-sotalol in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-d-sotalol0_top50_all.py - top 50 models
 of d-sotalol in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.        2\. Each*.py file should be opened using UCSF
 Chimera software: 3\. Missing
 data codes: None 4\. Specialized formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: dofetilide.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of dofetilide in neutral (0) or
 cationic (1) form docked to closed-state wild-type (WT), open-state WT,
 open-state Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-dofetilide1_top50_all.py – top 50 models of dofetilide in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-dofetilide1_top50_all.py - top 50 models of
 dofetilide in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-dofetilide0_top50_all.py – top 50
 models of dofetilide in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-dofetilide0_top50_all.py – top 50 models of
 dofetilide in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-dofetilide0_top50_all.py – top 50 models
 of dofetilide in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-dofetilide1_top50_all.py – top 50 models of
 dofetilide in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-dofetilide1_top50_all.py – top 50 models of
 dofetilide in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-dofetilide1_top50_all.py – top 50 models
 of dofetilide in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-dofetilide0_top50_all.py – top 50 models of
 dofetilide in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-dofetilide0_top50_all.py - top 50 models
 of dofetilide in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.      2\. Each*.py file should be opened using UCSF
 Chimera software: 3\. Missing
 data codes: None 4\. Specialized formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: flecainide.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of flecainide in neutral (0) or
 cationic (1) form docked to closed-state wild-type (WT), open-state WT,
 open-state Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel :
 open-hERG-F656A-flecainide1_top50_all.py – top 50 models of flecainide in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-flecainide1_top50_all.py - top 50 models of
 flecainide in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-flecainide0_top50_all.py – top 50
 models of flecainide in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-flecainide0_top50_all.py – top 50 models of
 flecainide in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-flecainide0_top50_all.py – top 50 models
 of flecainide in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-flecainide1_top50_all.py – top 50 models of
 flecainide in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-flecainide1_top50_all.py – top 50 models of
 flecainide in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-flecainide1_top50_all.py – top 50 models
 of flecainide in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-flecainide0_top50_all.py – top 50 models of
 flecainide in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-flecainide0_top50_all.py - top 50 models
 of flecainide in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.        2\. Each*.py file should be opened using UCSF
 Chimera software: 3\. Missing
 data codes: None 4\. Specialized formats or other abbreviations used: None
 \#########################################################################
   DATA-SPECIFIC INFORMATION FOR: l-sotalol.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of l-sotalol in neutral (0) or
 cationic (1) form docked to closed-state wild-type (WT), open-state WT,
 open-state Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:  
 open-hERG-F656A-l-sotalol1_top50_all.py – top 50 models of l-sotalol in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-l-sotalol1_top50_all.py - top 50 models of l-sotalol
 in cationic (1) form docked to hERG double Y652A/F656A mutant in an open
 state.      closed-hERG-WT-l-sotalol0_top50_all.py – top 50 models of
 l-sotalol in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-l-sotalol0_top50_all.py – top 50 models of
 l-sotalol in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-l-sotalol0_top50_all.py – top 50 models
 of l-sotalol in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-l-sotalol1_top50_all.py – top 50 models of
 l-sotalol in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-l-sotalol1_top50_all.py – top 50 models of
 l-sotalol in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-l-sotalol1_top50_all.py – top 50 models
 of l-sotalol in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-l-sotalol0_top50_all.py – top 50 models of
 l-sotalol in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-l-sotalol0_top50_all.py - top 50 models
 of l-sotalol in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.        2\. Each*.py file should be opened using UCSF
 Chimera software: 3\. Missing
 data codes: None 4\. Specialized formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: moxifloxacin.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of moxifloxacin in neutral (N) or
 zwitterionic (Z) form docked to closed-state WT, open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-moxifloxacinZ_top50_all.py – top 50 models of moxifloxacin
 in zwitterionic (Z) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-moxifloxacinZ_top50_all.py - top 50
 models of moxifloxacin in zwitterionic (Z) form docked to hERG double
 Y652A/F656A mutant in an open state.     
 closed-hERG-WT-moxifloxacinN_top50_all.py – top 50 models of moxifloxacin
 in neutral (N) form docked to WT hERG in a closed state.          
 open-hERG-WT-moxifloxacinN_top50_all.py – top 50 models of moxifloxacin in
 neutral (N) form docked to WT hERG in an open state.          
 open-hERG-Y652A-moxifloxacinN_top50_all.py – top 50 models of moxifloxacin
 in neutral (N) form docked to hERG Y652A mutant in an open state.     
 closed-hERG-WT-moxifloxacinZ_top50_all.py – top 50 models of moxifloxacin
 in zwitterionic (Z) form docked to WT hERG in a closed state.          
 open-hERG-WT-moxifloxacinZ_top50_all.py – top 50 models of moxifloxacin in
 zwitterionic (Z) form docked to WT hERG in an open state.          
 open-hERG-Y652A-moxifloxacinZ_top50_all.py – top 50 models of moxifloxacin
 in zwitterionic (Z) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-moxifloxacinN_top50_all.py – top 50 models of
 moxifloxacin in neutral (N) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-moxifloxacinN_top50_all.py - top 50
 models of moxifloxacin in neutral (N) form docked to hERG double
 Y652A/F656A mutant in an open state.        2\. Each*.py file should be
 opened using UCSF Chimera software:
 3\. Missing data codes: None 4\.
 Specialized formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: nifekalant.zip 1\. Contains RosettaLigand
 models (in UCSF Chimera .py format) of nifekalant in neutral (0) or
 cationic (1) form docked to closed-state WT, open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-nifekalant1_top50_all.py – top 50 models of nifekalant in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-nifekalant1_top50_all.py - top 50 models of
 nifekalant in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-nifekalant0_top50_all.py – top 50
 models of nifekalant in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-nifekalant0_top50_all.py – top 50 models of
 nifekalant in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-nifekalant0_top50_all.py – top 50 models
 of nifekalant in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-nifekalant1_top50_all.py – top 50 models of
 nifekalant in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-nifekalant1_top50_all.py – top 50 models of
 nifekalant in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-nifekalant1_top50_all.py – top 50 models
 of nifekalant in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-nifekalant0_top50_all.py – top 50 models of
 nifekalant in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-nifekalant0_top50_all.py - top 50 models
 of nifekalant in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.        2\. Each*.py file should be opened using UCSF
 Chimera software: 3\. Missing
 data codes: None 4\. Specialized formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: open-hERG-WT.pdb 1\. Contains top scoring
 model of the wild-type (WT) hERG (human Ether-à-go-go-Related Gene)
 channel in an open state in the PDB format.     2\. Each*.pdb file can be
 opened using UCSF Chimera or PyMol software:
 3\.
 Missing data codes: None 4\. Specialized formats or other abbreviations
 used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/amiodarone-PDBs files
 contained in top-score-PDBs.zip 1\. Contains amiodarone RosettaLigand
 models (in the PDB format) of amiodarone in neutral (0) or cationic (1)
 form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-amiodarone1_top50_1.pdb – top score model of amiodarone in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-amiodarone1_top50_1.pdb – top score model of
 amiodarone in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-amiodarone0_top50_1.pdb – top score
 model of amiodarone in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-amiodarone0_top50_1.pdb – top score model of
 amiodarone in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-amiodarone0_top50_1.pdb – top score model
 of amiodarone in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-amiodarone1_top50_1.pdb – top score model of
 amiodarone in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-amiodarone1_top50_1.pdb – top score model of
 amiodarone in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-amiodarone1_top50_1.pdb – top score model
 of amiodarone in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-amiodarone0_top50_1.pdb – top score model of
 amiodarone in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-amiodarone0_top50_1.pdb – top score
 model of amiodarone in neutral (0) form docked to hERG double Y652A/F656A
 mutant in an open state.      2\. Each*.pdb file can be opened using UCSF
 Chimera or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/d-sotalol-PDBs files
 contained in top-score-PDBs.zip 1\. Contains d-sotalol RosettaLigand
 models (in the PDB format) of d-sotalol in neutral (0) or cationic (1)
 form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-d-sotalol1_top50_1.pdb – top score model of d-sotalol in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-d-sotalol1_top50_1.pdb – top score model of
 d-sotalol in cationic (1) form docked to hERG double Y652A/F656A mutant in
 an open state.      closed-hERG-WT-d-sotalol0_top50_1.pdb – top score
 model of d-sotalol in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-d-sotalol0_top50_1.pdb – top score model of
 d-sotalol in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-d-sotalol0_top50_1.pdb – top score model
 of d-sotalol in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-d-sotalol1_top50_1.pdb – top score model of
 d-sotalol in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-d-sotalol1_top50_1.pdb – top score model of
 d-sotalol in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-d-sotalol1_top50_1.pdb – top score model
 of d-sotalol in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-d-sotalol0_top50_1.pdb – top score model of
 d-sotalol in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-d-sotalol0_top50_1.pdb – top score model
 of d-sotalol in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.      2\. Each*.pdb file can be opened using UCSF Chimera
 or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None
 \#########################################################################
   DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/dofetilide-PDBs files
 contained in top-score-PDBs.zip 1\. Contains dofetilide RosettaLigand
 models (in the PDB format) of dofetilide in neutral (0) or cationic (1)
 form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-dofetilide1_top50_1.pdb – top score model of dofetilide in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-dofetilide1_top50_1.pdb – top score model of
 dofetilide in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-dofetilide0_top50_1.pdb – top score
 model of dofetilide in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-dofetilide0_top50_1.pdb – top score model of
 dofetilide in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-dofetilide0_top50_1.pdb – top score model
 of dofetilide in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-dofetilide1_top50_1.pdb – top score model of
 dofetilide in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-dofetilide1_top50_1.pdb – top score model of
 dofetilide in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-dofetilide1_top50_1.pdb – top score model
 of dofetilide in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-dofetilide0_top50_1.pdb – top score model of
 dofetilide in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-dofetilide0_top50_1.pdb – top score
 model of dofetilide in neutral (0) form docked to hERG double Y652A/F656A
 mutant in an open state.      2\. Each*.pdb file can be opened using UCSF
 Chimera or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/flecainide-PDBs files
 contained in top-score-PDBs.zip 1\. Contains flecainide RosettaLigand
 models (in the PDB format) of flecainide in neutral (0) or cationic (1)
 form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-flecainide1_top50_1.pdb – top score model of flecainide in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-flecainide1_top50_1.pdb – top score model of
 flecainide in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-flecainide0_top50_1.pdb – top score
 model of flecainide in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-flecainide0_top50_1.pdb – top score model of
 flecainide in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-flecainide0_top50_1.pdb – top score model
 of flecainide in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-flecainide1_top50_1.pdb – top score model of
 flecainide in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-flecainide1_top50_1.pdb – top score model of
 flecainide in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-flecainide1_top50_1.pdb – top score model
 of flecainide in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-flecainide0_top50_1.pdb – top score model of
 flecainide in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-flecainide0_top50_1.pdb – top score
 model of flecainide in neutral (0) form docked to hERG double Y652A/F656A
 mutant in an open state.      2\. Each*.pdb file can be opened using UCSF
 Chimera or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/l-sotalol-PDBs files
 contained in top-score-PDBs.zip 1\. Contains l-sotalol RosettaLigand
 models (in the PDB format) of l-sotalol in neutral (0) or cationic (1)
 form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-l-sotalol1_top50_1.pdb – top score model of l-sotalol in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-l-sotalol1_top50_1.pdb – top score model of
 l-sotalol in cationic (1) form docked to hERG double Y652A/F656A mutant in
 an open state.      closed-hERG-WT-l-sotalol0_top50_1.pdb – top score
 model of l-sotalol in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-l-sotalol0_top50_1.pdb – top score model of
 l-sotalol in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-l-sotalol0_top50_1.pdb – top score model
 of l-sotalol in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-l-sotalol1_top50_1.pdb – top score model of
 l-sotalol in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-l-sotalol1_top50_1.pdb – top score model of
 l-sotalol in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-l-sotalol1_top50_1.pdb – top score model
 of l-sotalol in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-l-sotalol0_top50_1.pdb – top score model of
 l-sotalol in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-l-sotalol0_top50_1.pdb – top score model
 of l-sotalol in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.      2\. Each*.pdb file can be opened using UCSF Chimera
 or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/moxifloxacin-PDBs files
 contained in top-score-PDBs.zip 1\. Contains moxifloxacin RosettaLigand
 models (in the PDB format) of moxifloxacin in neutral (N) or zwitterionic
 (Z) form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-moxifloxacinZ_top50_1.pdb – top score model of
 moxifloxacin in zwitterionic (Z) form docked to hERG F656A mutant in an
 open state.      open-hERG-Y652A-F656A-moxifloxacinZ_top50_1.pdb – top
 score model of moxifloxacin in zwitterionic (Z) form docked to hERG double
 Y652A/F656A mutant in an open state.     
 closed-hERG-WT-moxifloxacinN_top50_1.pdb – top score model of moxifloxacin
 in neutral (0) form docked to WT hERG in a closed state.          
 open-hERG-WT-moxifloxacinN_top50_1.pdb – top score model of moxifloxacin
 in neutral (0) form docked to WT hERG in an open state.          
 open-hERG-Y652A-moxifloxacinN_top50_1.pdb – top score model of
 moxifloxacin in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-moxifloxacinZ_top50_1.pdb – top score model of
 moxifloxacin in zwitterionic (Z) form docked to WT hERG in a closed
 state.           open-hERG-WT-moxifloxacinZ_top50_1.pdb – top score model
 of moxifloxacin in zwitterionic (Z) form docked to WT hERG in an open
 state.           open-hERG-Y652A-moxifloxacinZ_top50_1.pdb – top score
 model of moxifloxacin in zwitterionic (Z) form docked to hERG Y652A mutant
 in an open state.      open-hERG-F656A-moxifloxacinN_top50_1.pdb – top
 score model of moxifloxacin in neutral (0) form docked to hERG F656A
 mutant in an open state.     
 open-hERG-Y652A-F656A-moxifloxacinN_top50_1.pdb – top score model of
 moxifloxacin in neutral (0) form docked to hERG double Y652A/F656A mutant
 in an open state.      2\. Each*.pdb file can be opened using UCSF Chimera
 or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None
 \#########################################################################
 DATA-SPECIFIC INFORMATION FOR: top-score-PDBs/nifekalant-PDBs files
 contained in top-score-PDBs.zip 1\. Contains nifekalant RosettaLigand
 models (in the PDB format) of nifekalant in neutral (0) or cationic (1)
 form docked to closed-state wild-type (WT), open-state WT, open-state
 Y652A, F656A, and double Y652A/F656A mutants of the hERG (human
 Ether-à-go-go-Related Gene) channel:
 open-hERG-F656A-nifekalant1_top50_1.pdb – top score model of nifekalant in
 cationic (1) form docked to hERG F656A mutant in an open state.     
 open-hERG-Y652A-F656A-nifekalant1_top50_1.pdb – top score model of
 nifekalant in cationic (1) form docked to hERG double Y652A/F656A mutant
 in an open state.      closed-hERG-WT-nifekalant0_top50_1.pdb – top score
 model of nifekalant in neutral (0) form docked to WT hERG in a closed
 state.           open-hERG-WT-nifekalant0_top50_1.pdb – top score model of
 nifekalant in neutral (0) form docked to WT hERG in an open
 state.           open-hERG-Y652A-nifekalant0_top50_1.pdb – top score model
 of nifekalant in neutral (0) form docked to hERG Y652A mutant in an open
 state.      closed-hERG-WT-nifekalant1_top50_1.pdb – top score model of
 nifekalant in cationic (1) form docked to WT hERG in a closed
 state.           open-hERG-WT-nifekalant1_top50_1.pdb – top score model of
 nifekalant in cationic (1) form docked to WT hERG in an open
 state.           open-hERG-Y652A-nifekalant1_top50_1.pdb – top score model
 of nifekalant in cationic (1) form docked to hERG Y652A mutant in an open
 state.      open-hERG-F656A-nifekalant0_top50_1.pdb – top score model of
 nifekalant in neutral (0) form docked to hERG F656A mutant in an open
 state.      open-hERG-Y652A-F656A-nifekalant0_top50_1.pdb – top score
 model of nifekalant in neutral (0) form docked to hERG double Y652A/F656A
 mutant in an open state.      2\. Each*.pdb file can be opened using UCSF
 Chimera or PyMol software: 
 3\. Missing data codes: None 4\. Specialized
 formats or other abbreviations used: None ## Sharing/Access information
 Supplement to a published version of the manuscript entitled
 "Structural Modeling of hERG Channel – Drug Interactions Using
 Rosetta" contains zipped file (.zip format) containing: * Top scoring
 models of WT hERG in closed and open states. * Subfolders contain a drug
 (amiodarone, d-sotalol, dofetilide, flecainide, l-sotalol, moxifloxacin,
 and nifekalant) in neutral (0) or charged (1) form for amiodarone,
 d-sotalol, dofetilide, flecainide, l-sotalol, and nifekalant or in neutral
 (N) or zwitterionic (Z) form for moxifloxacin docked to closed WT, open
 WT, Y652A, F656A, and Y652A and F656A double mutant models of hERG. ##
 Code/Software UCSF Chimera software
 () should be used to open models
 in UCSF Chimera .py format. UCSF Chimera or PyMol software can be used to
 open models in PDB format.