DOI: 10.25338/b8f342
title: Data from: Elucidation of molecular mechanisms of sex-based arrhythmias

description: Female sex has been shown to be an independent risk factor for both
 inherited and acquired heart rhythm abnormalities, such as long QT
 syndrome (LQTS) and associated arrhythmias. Notably, female sex is a key
 element in up to 70% prevalence of drug-induced acquired LQTS, However,
 fundamental molecular mechanisms that explain this phenomenon are not well
 understood. Previous experimental and clinical studies suggested that it
 is likely related to differential levels of sex hormones (estradiol,
 progesterone and testosterone) playing opposite roles in pro-arrhythmia
 proclivities, exacerbating or mitigating effects of mutations or drugs on
 cardiac ion channels.  In the American Heart Association (AHA)
 sponsored career development award 19CDA34770101 "Elucidation of
 molecular mechanisms of sex-based arrhythmias" we focused on hormone
 interactions with the human Kv11.1 potassium channel (encoded by the hERG
 - human Ether-à-go-go-Related Gene), a major contributor to cardiac action
 potential repolarization and an anti-target for diverse drug molecules. We
 performed a comprehensive set of in silico atomistic modeling and
 simulations on hERG structure and function modulation by sex hormones in
 combination with hERG channel blockers with different proclivities for
 arrhythmogenesis.  These studies were informed by and will also
 guide electrophysiological experiments on cardiomyocytes and
 hERG-expressing HEK cells by our collaborators.  Molecular
 dynamics (MD) simulation and molecular docking data, presented here and
 validated by electrophysiological recordings, will provide us with
 quantitative estimates of such hormone modulatory effects and will be used
 for elucidation of molecular mechanisms of sex-dependent heart rhythm
 abnormalities and thus the ways to combat them via rational design of
 sex-specific cardiac safe pharmaceuticals and/or their dose adjustments.
 The dataset contains MD simulations of hERG channel - hormone and drug
 interactions as well as their analyses. Multi-microsecond-long umbrella
 sampling MD simulations as well as fragment-based Site-Identification by
 Ligand Competitive Saturation (SILCS) docking results were performed and
 presented here. 
description: The dataset was collected using molecular dynamcis
 (MD) simulations and fragment-based Site-Identification by Ligand
 Competitive Saturation (SILCS) molecular docking calculations of the
 wild-type hERG potassium channel model based on the cryogenic electron
 microscopy (cryo-EM structure) with PDB ID: 5VA2. Pore and voltage sensing
 domain residues 405-668 were used in the model. Rosetta structural
 modeling was used for de novo missing loop
 building. hERG channel models in a ~260
 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer
 soaked by 0.15 M aqueous KCl solution and a  hormone molecule initially
 placed  in aqueous solution under .  All simulations were run using NAMD
 2.13 or later in the <em>NPT</em> ensemble at 310 K and 1 atm
 pressure using Nose-Hoover thermostat and Langevin piston barostat.
 Standard cutoff scheme and particle mesh Ewald (PME) will be used for
 non-bonded interactions. Standard CHARMM biomolecular force fields (C36
 for lipids, CHARMM36m for protein and standard CHARMM ion parameters) and
 TIP3P water model were used for compatibility with our previous
 studies. One equilibration and 5 steered MD (SMD) “pulling”
 90-ns long simulations were performed for each hormone (estradiol and
 dihydrotestosterone) using our previously developed protocol
 . The final frames from these simulations was be used
 as starting points for umbrealla sampling MD (US-MD) runs The simulation
 length was chosen to reach a well equilibrated system based on our prior
 experience. <em style="font-family:Calibri , sans-serif;">We needed to perform at least 5 SMD simulations with different initial
 conditions to avoid a bias in initial drug orientations in subsequent
 US-MD runs</em>.
 
 For US-MD
 simularions, we used hERG channel model in a POPC membrane solvated by
 0.15 M aqueous KCl + 1 drug placed at different
 <em>z</em> positions along
 the channel axis in 0.5 Å intervals.  The same force field
 and general MD simulation parameters as described above was used. US-MD
 simulations with harmonic restraints on drug center of mass (COM) with
 respect to C<sub style="font-family:Calibri , sans-serif;">a</sub> COM of hERG selectivity filter (SF) (<sup style="font-family:Calibri , sans-serif;">624</sup>SVGFG) residues were performed to compute drug free energy and diffusion coefficient profiles across the channel pore. Weak 0.2 kcal/mol/Å<sup style="font-family:Calibri , sans-serif;">2</sup> positional restraints for the SF backbone and the whole pore domain C<sub style="font-family:Calibri , sans-serif;">a</sub> atoms were used as was done in our previous simulations to preserve a channel conformational state and also minimize their effect on drug binding.  We used 90 US-MD simulation windows covering a range -50 £ <em>z</em> £ -5.5 Å, from the bottom of the SF and down through the pore, extending far enough into the solvent to get bulk-like free energy and diffusion coefficient values. Starting structures were taken from the 5 SMD simulations described above, choosing one of them at random for each <em style="font-family:Calibri , sans-serif;">z </em>position to avoid an initial bias. 40 ns per window with an initial ~10 ns as equilibration, equivalent to amount of sampling used in similar studies  and in our previous calculations, where 40 ns per US-MD window was barely sufficient to reach a desired convergence.  For SILCS simulations using 2022.2 software we used hERG channel models in a ~220 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) & 13 cholesterol lipid bilayer soaked by 0.15 M aqueous KCl solution along with multiple molecules of 9 different co-solvents (methanol, benzene etc.).  All simulations were run using Gromacs 2020.2 or later in the <em>NPT</em> ensemble at 310 K and 1 atm pressure. Standard cutoff scheme and particle mesh Ewald (PME) were used for non-bonded interactions. Standard CHARMM biomolecular force fields (C36 for lipids, CHARMM36m for protein and standard CHARMM27 ion parameters) and TIP3P water model were used for compatibility with our previous studies . Ten 100-ns MD simulations will be performed for each channel model as dictated by established SILCS protocol. Each 1 ns run is intervened by 200,000 steps of Grand Canonical Monte Carlo (GCMC) for co-solvent molecule insertion/deletion and translations/rotations. This was followed by SILCS MC docking of drug and/or hormone molecules into the hERG channel pore. Top-scoring (most favorable binding free energy) hERG channel - drug structures are available for further analysis.
description: PDB files contaning molecular structures can be opened with
 multiple molecular modeling and visualization software such as VMD,  UCSF
 Chimera or ChimeraX, PyMol etc.  Protein structure
 files (PSF) containing system topologies and molecular dynamics (MD)
 simulation trajectory files in the binary DCD format can be opened using
 VMD or PyMol software.  Input and output files can be
 opened using any text editor.  
  
description: # Title of Dataset Data for the grant "Elucidation of molecular
 mechanisms of sex-based arrhythmias" This dataset is associated with
 the In the American Heart Association (AHA) sponsored career development
 award 19CDA34770101 "Elucidation of molecular mechanisms of sex-based
 arrhythmias, in which we focused on hormone and/or drug interactions with
 the human Kv11.1 potassium channel (encoded by the hERG - human
 Ether--go-go-Related Gene), a major contributor to cardiac action
 potential repolarization and an anti-target for diverse drug molecules.
 The dataset contains MD simulations of hERG channel - hormone and/or drug
 interactions as well as their analyses. Multi-microsecond-long umbrella
 sampling MD simulations as well as fragment-based Site-Identification by
 Ligand Competitive Saturation (SILCS) docking results were performed and
 presented here. ## Description of the data and file structure The dataset
 includes gzipped tar ball files, which contain multiple files, which need
 to be extracted and uncompressed.
 **herg_o2_e2b_zm50_namd_u01_r1_50.tar.gz.partaa** - gzipped tar ball file
 (part 1/2) for the hERG channel - estradiol (E2b) interactions using
 all-atom umbrella sampling molecular dynamics (US-MD) simulations
 **herg_o2_e2b_zm50_namd_u01_r1_50.tar.gz.partab** - gzipped tar ball file
 (part 2/2) for the hERG channel - estradiol (E2b) interactions using
 all-atom umbrella sampling molecular dynamics (US-MD) simulations
 **herg_o2_dht_zm50_namd_u01_r1_70_partial.tar.gz** - gzipped tar ball file
 for the hERG channel - dihydrotestosterone (DHT) interactions using
 all-atom umbrella sampling molecular dynamics (US-MD) simulations.
 **herg_o2_dht_zm50_namd06_pullx_us0x.tar.gz** - gzipped tar ball file for
 the hERG channel - dihydrotestosterone (DHT) interactions using initial 50
 ns-long equilibration and five 90-ns-long pulling (steered MD) runs.
 **herg_o2_e2b_zm50_namd06_pullx_us0x.tar.gz** - gzipped tar ball file for
 the hERG channel - estradiol (E2b) interactions using initial 50 ns-long
 equilibration and five 90-ns-long pulling (steered MD) runs.
 **hormone_herg_silcs_docking_.tar.gz** - gzipped tar ball file for the
 hERG channel - hormone and/or drug interactions using SILCS MC
 fragment-based molecular docking. Extraction and decompression
 instructions for .tar.gz: tar xvfz FILE_NAME.tar.gz Or gunzip
 FILE_NAME.tar.gz tar xvf ILE_NAME.tar Split tar.gz files (.partaa and
 .partb) need to be combined first cat FILE_NAME.tar.gz.partaa
 FILE_NAME.tar.gz.partab &gt; FILE_NAME.tar.gz After extraction of all
 those files the following folders will be created:
 herg_o2_e2b_zm50_namd_u01_r1_50/ herg_o2_dht_zm50_namd_u01_r1_70_partial/
 herg_o2_dht_zm50_namd06_pullx_us0x/ herg_o2_e2b_zm50_namd06_pullx_us0x/
 hormone_herg_docking/ Below is the description of each of these folders as
 well as subfolders and files within them. There are also README files
 within some of those folders with more detailed information. **Folder
 herg_o2_e2b_zm50_namd_u01_r1_50/** - data for all-atom umbrella sampling
 molecular dynamics (US-MD) simulations of hERG channel - estradiol (E2b)
 interactions. 90 US-MD windows were used with 50 ns per window, 4,500 ns
 of MD simulation time in total. Initial and final coordinates in the PDB
 and NAMD binary (.coor) formats, binary velocity (.vel) and system size
 (.xtc) files, protein structure files (.psf), NAMD input (.inp) and output
 (.out or .log) files., trajectory files for collective variables (.traj),
 force field parameter files (.par) are included for each US-MD run. Binary
 trajectory (.dcd) files are not included. ***Subfolders 1/ to 90/***
 contain data for each of US-MD runs 1 to 90 corresponding to Z value of
 -50 to -5.5 Angstrom. Z distance is counted with respect to center of mass
 (COM) of C-alpha atoms of selectivity filter (SF) residues 624-628. In
 each folder there are runs 1-50, each of them corresponds to 1 ns of the
 simulation. File names are:*step9.[run_number]_production.[extension]* For
 instance, for window 5 and run 10 files are: 5/step9.10_production.col -
 NAMD collective variable (colvar) file, text format, used by NAMD software
 and can be read by NAMD or text editor 5/step9.10_production.colvars.state
 - NAMD collective variable (colvar) state file, text format, output of
 NAMD software, contains latest values of colvars at the end of each run
 5/step9.10_production.colvars.traj - NAMD collective variable (colvar)
 trajectory file, text format, output of NAMD software, contains trajectory
 of colvars for the whole run 5/step9.10_production.coor - NAMD binary
 coordinate file at the end of each run, can be read by VMD or NAMD
 software after reading PDB or PSF file containing atom names and topology
 5/step9.10_production.inp - NAMD input file, text format, can be read
 using text editor and by NAMD software 5/step9.10_production.log - NAMD
 output file, text format, can be read using text editor
 5/step9.10_production.vel - NAMD binary velocity file at the end of each
 file, can be read by VMD or NAMD software after reading PDB or PSF file
 containing atom names and topology. 5/step9.10_production.xsc - NAMD unit
 cell file (x, y, z and angles) at the end of each run, text file, can be
 read using text editor, NAMD and VMD software 5/step9.10_production.xst
 NAMD unit cell file (x, y, z and angles) trajectory for the entire run,
 text file, can be read using text editor, NAMD and VMD software For each
 window we also have initial coordinates and velocity files
 5/step8.5_production.coor - initial NAMD binary coordinate file for each
 US-MD window, can be read by VMD or NAMD software after reading PDB or PSF
 file containing atom names and topology 5/step8.5_production.vel - initial
 NAMD binary velocity file for each US-MD window, can be read by VMD or
 NAMD software after reading PDB or PSF file containing atom names and
 topology 5/step8.5_production.xsc - initial NAMD unit cell file (x, y, z
 and angles) at the end of each run, text file, can be read using text
 editor, NAMD and VMD software. 5/step5_assembly.namd.str - NAMD stream
 file, text format, can be read by NAMD software and text editor
 5/checkfft.str - NAMD stream file for fast Fourier transform (FFT)
 parameters, text format, can be read by NAMD software and text editor
 5/production_restraint.namd.col - NAMD collective variable (colvar)
 initial file, text format, used by NAMD software and can be read by NAMD
 or text editor ***Subfolder all_inp/*** contain input files and job
 submission scripts, common for all US-MD windows or templates (.templ)
 used to generate ones specific for each US-MD run. All files are in text
 format and can be read by any text editor. all_inp/checkfft.str - NAMD
 stream file for fast Fourier transform (FFT) parameters, text format, can
 be read by NAMD software and text editor
 all_inp/herg_mx0_cometgpu_us_wx_02.qsub.templ - SLURM job submission
 script template for SDSC Comet GPU nodes
 all_inp/herg_mx0_comet_us_wx_02.qsub.templ - SLURM job submission script
 template for SDSC Comet CPU nodes
 all_inp/production_restraint.namd.col.templ - NAMD stream file template,
 text format, can be read by NAMD software and text editor
 all_inp/step5_assembly.namd.str - NAMD collective variable template file,
 text format all_inp/step9.1_production.inp.templ - NAMD input file
 template for run #1 all_inp/step9_production.inp - NAMD input file
 template for runs #2-50 ***Subolder toppar/*** contains CHARMM parameter
 files in text format, all files can be read by any text editor, NAMD or
 CHARMM software. par_*.prm - parameter files for different biomolecular
 systems (proteins, lipids etc.). toppar_*.str - auxiliary parameter files
 for specific molecules (e.g., water). ***Subfolder restraints/*** contains
 NAMD files for restraints used in the MD simulations. All files are in
 text format and can be read by any text editor, NAMD or CHARMM software.
 *.ref files are reference coordinates (in the PDB text format) with
 restraints written as a previous to the last column (e.g., 1.00 -
 restraint, 0.00 - no restraint) for each atom. write_ca_rest.tcl is VMD
 script in the text format, which generates those restraint files. dihe.txt
 is restraint file for dihedral angles. ***Subfolder e2b/*** contains
 CHARMM topology (e2b.rtf) and parameter (e2b.prm) files for estradiol in
 the text format, can be read by NAMD or CHARMM software. ***Subfolder
 pmf_convergence/*** contains text files of US_MD collective variables to
 compute free energy or potential of mean force (PMF) profile using
 weighted histogram analysis method (WHAM). pmf_[win_num]_[run_num].dat are
 text data files for US_MD window and run number. wham_old2_newf.f90 - WHAM
 program script written in Fortran 90, can be compiled using GNU Fortran.
 wham_old2_newf.exe - WHAM program executable in the binary format, can be
 run on x86 computers using Linux wham.inp - text input file for WHAM
 program wham_clean.run - shell script in text format to remove unneeded
 files. win_ene_hist2o.run - shell script in text format to generate PMF
 histogram. ***Files in the parent subfolder ./*** check_max_run.run -
 shell script in text format to check max run for each US-MD window
 convert_NAMD2WHAM*.sh - shell script in text format to convert colvar
 trajectories from NAMD to WHAM program format copy_run_qsub_us_windows.run
 - - shell script in text format to copy US-MD window files e2b*.qsub -
 queue submission scripts for different platforms and for different US-MD
 windows (w#). edit_pmf.sh - shell script in text format to edit
 information in WHAM colvar trajectory files if needed.
 make_all_us_windows.run - shell script in text format to generate all
 US-MD windows random_num.txt - text file with random numbers. README.txt -
 text file with description of MD simulation procedure.
 shuffle_windows_new.py - Python script in text format to generate
 non-repeating random numbers for subsequent US-MD windows.
 shuffle_windows.py - Python script in text format to generate random
 numbers for subsequent US-MD windows (not used). step5_assembly.namd.pdb -
 Initial molecular coordinates in the PDB text NAMD compatible format.
 step5_assembly.pdb - Initial molecular coordinates in the PDB text
 original format. step5_assembly.psf - CHARMM protein structure file (PSF)
 in the text format. step5_assembly.xplor_ext.psf - CHARMM protein
 structure file (PSF) in the extended text format. **Folder
 herg_o2_dht_zm50_namd_u01_r1_70_partial/** - data for all-atom umbrella
 sampling molecular dynamics (US-MD) simulations of the hERG channel -
 dihydrotestosterone (DHT) interactions. 90 US-MD windows were used with up
 to 70 ns per window, 6,300 ns of MD simulation time in total. Initial and
 final coordinates in the PDB and NAMD binary (.coor) formats, binary
 velocity (.vel) and system size (.xtc) files, protein structure files
 (.psf), NAMD input (.inp) and output (.out or .log) files, trajectory
 files for collective variables (.traj), force field parameter files (.par)
 are included for each US-MD run. Binary trajectory (.dcd) files are not
 included. Some files not important for free energy and diffusion
 coefficient calculation analysis are missing but can be re-generated using
 new runs if needed. ***Subfolders 1/ to 90/*** contain data for each of
 US-MD runs 1 to 90 corresponding to Z value of -50 to -5.5 Angstrom. Z
 distance is counted with respect to center of mass (COM) of C-alpha atoms
 of selectivity filter (SF) residues 624-628. In each folder there are runs
 1-30 (windows 1-50) or 1-15 (windows 51-90), each of them corresponds to 1
 ns of the simulation. ***Subfolder all_inp/*** contain input files and job
 submission scripts, common for all US-MD windows or templates (.templ)
 used to generate ones specific for each US-MD run. All files are in text
 format and can be read by any text editor. ***Subolder toppar/*** contains
 CHARMM parameter files in text format, all files can be read by any text
 editor, NAMD or CHARMM software. par_*.prm - parameter files for different
 biomolecular systems (proteins, lipids etc.). toppar_*.str - auxiliary
 parameter files for specific molecules (e.g., water). ***Subfolder
 restraints/*** contains NAMD files for restraints used in the MD
 simulations. All files are in text format and can be read by any text
 editor, NAMD or CHARMM software. ***Subfolder dht/*** contains CHARMM
 topology (dht.rtf) and parameter (dht.prm) files for dihydrotestosterone
 in the text format, can be read by NAMD or CHARMM software. ***Subfolder
 pmf_convergence/*** contains text files of US_MD collective variables to
 compute free energy or potential of mean force (PMF) profile using
 weighted histogram analysis method (WHAM). ***Files in the parent
 subfolder ./*** check_max_run.run - shell script in text format to check
 max run for each US-MD window convert_NAMD2WHAM*.sh - shell script in text
 format to convert colvar trajectories from NAMD to WHAM program format
 copy_run_qsub_us_windows.run - - shell script in text format to copy US-MD
 window files dht*.qsub - queue submission scripts for different platforms
 and for different US-MD windows (w#). edit_pmf.sh - shell script in text
 format to edit information in WHAM colvar trajectory files if needed.
 make_all_us_windows.run - shell script in text format to generate all
 US-MD windows random_num.txt - text file with random numbers. README.txt -
 text file with description of MD simulation procedure.
 shuffle_windows_new.py - Python script in text format to generate
 non-repeating random numbers for subsequent US-MD windows.
 shuffle_windows.py - Python script in text format to generate random
 numbers for subsequent US-MD windows (not used). step5_assembly.namd.pdb -
 Initial molecular coordinates in the PDB text NAMD compatible format.
 step5_assembly.pdb - Initial molecular coordinates in the PDB text
 original format. step5_assembly.psf - CHARMM protein structure file (PSF)
 in the text format. step5_assembly.xplor_ext.psf - CHARMM protein
 structure file (PSF) in the extended text format.
 all_ligand_tumble_hERG.tcl - example CMD TCL script for ligand tumbling
 analysis (it was used for a different ligand and needs to be modified for
 DHT if needed). Please see detailed file type description for the folder
 herg_o2_e2b_zm50_namd_u01_r1_50/ above. **Folder
 herg_o2_dht_zm50_namd06_pullx_us0x/** - data for initial 50 ns-long
 equilibration and five 90-ns-long pulling (steered MD) runs of the hERG
 channel - dihydrotestosterone (DHT) interactions.\ Initial and final
 coordinates in the PDB and NAMD binary (.coor) formats, binary velocity
 (.vel) and system size (.xtc) files, protein structure files (.psf), NAMD
 input (.inp) and output (.out or .log) files., trajectory files for
 collective variables (.traj), force field parameter files (.par) are
 included for each US-MD run. Binary trajectory (.dcd) files are not
 included. ***Subfolder CHARMM-GUI/*** has files in text format generated
 by input generator, bilayer builder by
 [www.charmm-gui.org](http://www.charmm-gui.org) ***Subfolder initial/***
 contains CHARMM scripts (all in text format) to generate initial hERG
 channel - hormone structure ***Subfolder namd06/*** contains NAMD files
 for 50 ns-long equilibration ***Subfolders namd_pullf1[1-5]/*** contain
 NAMD files for five 90-ns-long pulling (steered MD) runs. ***Subfolder
 namd_us02/*** contains NAMD files for US-MD simulation (initial files and
 templates only). Please see detailed description of file types for the
 description of the folder herg_o2_e2b_zm50_namd_u01_r1_50/ above and
 detailed instructions on setting up and running simulations in the file
 README.txt **Folder herg_o2_e2b_zm50_namd06_pullx_us0x**/ - data for
 initial 50 ns-long equilibration and five 90-ns-long pulling (steered MD)
 runs of the hERG channel - estradiol (E2b) interactions. Initial and final
 coordinates in the PDB and NAMD binary (.coor) formats, binary velocity
 (.vel) and system size (.xtc) files, protein structure files (.psf), NAMD
 input (.inp) and output (.out or .log) files., trajectory files for
 collective variables (.traj), force field parameter files (.par) are
 included for each US-MD run. Binary trajectory (.dcd) files are not
 included. ***Subfolder CHARMM-GUI/*** has files in text format generated
 by input generator, bilayer builder by
 [www.charmm-gui.org](http://www.charmm-gui.org) ***Subfolder initial/***
 contains CHARMM scripts (all in text format) to generate initial hERG
 channel - hormone structure ***Subfolder namd06/*** contains NAMD files
 for 50 ns-long equilibration ***Subfolders namd_pullf1[1-5]/*** contain
 NAMD files for five 90-ns-long pulling (steered MD) runs. ***Subfolder
 namd_us02/*** contains NAMD files for US-MD simulation (initial files and
 templates only). Please see detailed description of file types for the
 description of the folder herg_o2_e2b_zm50_namd_u01_r1_50/ above and
 detailed instructions on setting up and running simulations in the file
 README.txt **Folder hormone_herg_docking/** - data for SILCS-MC
 fragment-based molecular docking the hERG channel - hormone and/or drug
 interactions. Only final PDB files containing hERG channel and drug and/or
 hormone molecules for top-scoring (lowest interaction energy) binding
 poses are included. All files are in the text PDB format and can be read
 by any text editor, multiple molecular visualization software (VMD, USCF
 Chimera or ChimeraX, PyMol etc.) ## Sharing/Access information Links to
 other publicly accessible locations of the data: None Data was derived
 from the following sources: None ## Code/Software All-atom molecular
 dynamics (MD) simulations were performed using nanoscale molecular
 dynamics (NAMD) software, version 2.13 or 2.14 and were analyzed using
 visual molecular dynamics (VMD) software version 1.9.3. Fragment-based
 Site-Identification by Ligand Competitive Saturation (SILCS) molecular
 docking calculations used software 2022.2. SILCS fragment-generation MD
 simulation runs used Grimaces software version 2020.2 or later.