DOI: 10.5061/dryad.w0vt4b91z
title: Data from: Modeling stereospecific drug interactions with beta-adrenergic receptor

description: Beta-adrenergic receptors (βARs) are G protein-coupled receptors that
 regulate processes such as heart rhythm and vascular tone by binding
 agonists like norepinephrine, inducing downstream signaling pathways. Beta
 blockers antagonize βARs, reducing heart rate and lowering vascular tone.
 We developed a new Rosetta structural modeling protocol to create
 state-specific models of β1AR and investigated its atomistic-scale
 interactions with beta-blocker stereoisomers: d- and l-sotalol, as well as
 R- and S-propranolol. Our combined molecular dynamics (MD) simulations and
 docking protocol effectively captured the differences in stereoisomer
 specificity in binding to β1AR. Binding energetics results favored
 l-sotalol and S-propranolol, consistent with experimental findings showing
 d-sotalol has significantly lower affinity for beta-adrenergic receptors
 than l-sotalol. The entropy term was identified as the primary factor
 driving enantiomer binding specificity, with higher entropy costs for
 d-sotalol and R-propranolol due to their unfavorable chiral structures.
 Simulations demonstrated that subtle differences in enantiomers lead to
 distinct β1AR conformations, with d and R enantiomers causing larger
 structural changes than l and S enantiomers. Specifically, sotalol affects
 ICL2 and propranolol affects ICL1. The distance between TM4 and TM6 also
 exhibited different distributions among enantiomers, indicating varying
 strengths in stabilizing specific GPCR states. The outer vestibule of the
 receptor may play a crucial role in the stereoselectivity of small drugs,
 evidenced by fewer contacts between d-sotalol and ECL2 residues compared
 to l-sotalol. This study provides a foundation for understanding the
 stereospecificity of beta blockers for βARs, which are important
 pharmacological targets, and could be extended to other drug classes and
 receptor types.
description: The input files for structure modeling and MD simulations, output
 files, and MD simulation trajectories were collected and
 presented. 
description: # Data from: Modeling stereospecific drug interactions with
 beta-adrenergic receptor The dataset focuses on molecular modeling and
 simulations of the beta-1 adrenergic receptor interacting with different
 stereoisomers of the beta-blockers sotalol and propranolol. It includes
 input files, setup configurations, and key output files used for Rosetta
 structural modeling, RosettaLigand docking, conventional all-atom
 molecular dynamics (MD) equilibration and production runs, as well as
 Gaussian accelerated MD (GaMD) simulations. Key data files for simulation
 setup and analysis are included, along with scripts used to perform these
 analyses. Files with the ".sh" extension are executable shell
 scripts that can be run from the command line. Example output files and
 short MD simulation trajectories are also provided. Users can visualize
 the trajectories using software such as VMD. The analyses and results
 generated from this dataset will be published in peer-reviewed journals,
 with appropriate links provided to this dataset. ## Description of the
 data and file structure ### Dataset ICL3\_modeling.zip (model preparation
 for intracellular loop 3 (ICL3)) \|-
 submit_MEF_kic_with_frags_icl3.atomate_jrdd.qsub (ICL3 loop building SLURM
 job submission script) \|- 7bvq_template_ptrd.pdb (input pdb for ICL3
 building, but this one without ICL3, only the helices) \|-
 7bu6_template_ptd_dummy_loop.pdb (input pdb for extracting dummy ICL3) \|-
 7bvq_template_ptd_dummy_loop.pdb (loop building input pdb with a dummy
 ICL3, the modeling protocol required coordinates for the loop already be
 present) \|- adding_dummy_loop.py (Python code to add dummy ICL3 to
 7bvq_template_ptrd.pdb) \|-
 modeling_stages_b1arr_versus_b1ara_2024_resave.py (Miscellaneous Python
 code) \|- loopmodel_inp (Input files for Rosetta loop modeling) || -
 icl3.loop (Miscellaneous file for loop building) || - hb1arr_target.span (
 File indicating location of lipid membrane for target protein) || -
 hb1arr_target.fasta (Protein sequence file in the FASTA format ) || -
 disulfides.ss (File indicating disulfife bridge location) || -
 ab_inito.map (map file for loop building defining region of protein to be
 completely rebuilt) || - 7bvq_template_ptd_dummy_loop.span (File
 indicating location of lipid membrane for the template protein) || -
 7bvq_template_ptd_dummy_loop.pdb (loop building input pdb with a dummy
 ICL3, the modeling protocol required coordinates for the loop already be
 present) || - hb1arr_target-grishn.aln (Protein sequence alignment file)
 \|- hb1arr.200.03.3mers (Protein 3-residue fragments used for loop
 building) \|- hb1arr.200.09.9mers ( Protein 9-residue fragments used for
 loop building) \|- kic_with_frags_mef.xml (Please refer to the one in
 Dataset ### C\_terminal\_modeling.zip. Rosetta script in the XML format
 for KIC loop building with fragments) \|- stage1_membrane.wts (Membrane
 weights for stage 1 of loop building) \|- stage2_membrane.wts (Membrane
 weights for stage 2 of loop building) \|- stage3_rlx_membrane.wts
 (Membrane weights for stage 3 of loop building) \|- example_output
 (example output file after performed loop building) || -
 7bvq_template_ptd_dummy_loop.pdb (loop building input pdb with a dummy
 ICL3, the modeling protocol required coordinates for the loop already be
 present) || - 2021-05-11_7bvq_hb1arr_icl3_kWF_MEF_production-1.silent
 (Compressed protein structure archive in the Rosetta Silent format) || -
 2021-05-11_7bvq_hb1arr_icl3_kWF_MEF_production-1.fsc (File with Rosetta
 scores for building protein structures) || -
 2021-05-11_7bvq_hb1arr_icl3_kWF_MEF_production-1.silent.merge.tmp
 (Temporary file used for protein structure archive merging) || -
 2021-05-11_7bvq_hb1arr_icl3_kWF_MEF_production-1.log (Log file from
 protein structure building) ### Dataset C\_terminal\_modeling.zip (model
 preparation for C terminus buidling) \|-
 submit_MEF_kwf_cterm.atomate_jrdd.qsub (SLURM job submission script for C
 terminus building) \|- all_inp (All input files used for C terminus
 building) || - disulfides.ss (File indicating disulfide bridge location)
 || - hb1arr_target.span (File indicating location of lipid membrane for
 the target protein) || -
 hb1arr_7bvq_icl3_built_4470002_dummy_cterm_plus_ala.span (File indicating
 location of lipid membrane for the template protein) || -
 hb1arr_7bvq_icl3_built_4470002_dummy_cterm_plus_ala.pdb (input pdb file
 with a built ICL3 and dummy C terminus, the modeling protocol required
 coordinates for the terminus already be present) || -
 hb1arr_target-grishn.aln (Protein sequence alignment file) || -
 hb1arr_target.fasta (Target protein sequence file in the FASTA format) ||
 - ab_inito.map (map file for loop building) \|- hb1arr.200.03.3mers
 (Protein 3-residue fragments used for C-terminus building) \|-
 hb1arr.200.09.9mers (Protein 9-residue fragments used for C-terminus
 building) \|- kic_with_frags_mef.xml (Rosetta script in the XML format for
 KIC C-terminus building with fragments) \|- stage1_membrane.wts (Membrane
 weights for stage 1 of C-terminus building) \|- stage2_membrane.wts
 (Membrane weights for stage 2 of C-terminus building) \|-
 stage3_rlx_membrane.wts (Membrane weights for stage 3 of C-terminus
 building) \|- cluster_decoys.sh (Clusters structures (decoys) from a
 Rosetta silent file based on structural similarity, with a user-defined
 RMSD radius.) \|- pre-merge_rename.sh (Merge the icl3 and C_terminal) \|-
 example_output (example output file after performed C-terminus building )
 || - hb1arr_7bvq_icl3_built_4470002_dummy_cterm_plus_ala.pdb (input pdb
 file with a built ICL3 and dummy C terminus, the modeling protocol
 required coordinates for the terminus already be present) || -
 2021-05-17_7bvq_kwf_mef_cterm-1.silent (Compressed protein structure
 archive in the Rosetta Silent format) || -
 2021-05-17_7bvq_kwf_mef_cterm-1.fsc (File with Rosetta scores for built
 protein structures) || - 2021-05-17_7bvq_kwf_mef_cterm-1.log (Log file for
 built protein structures) ### Dataset ligand\_dock\_norepinephrine.zip
 (RosettaLigand docking of norepinephrine to beta 1AR) \|- clean_pdb_builds
 (Initial files for ligand + receptor complex, receptors include C-terminal
 and ICL3 loops, the major helix part of the receptors are based on
 structures from protein data bank, users can match up the files with the
 source based on the second part of the file name (i.e., 3SN6 or 7BVQ) ) ||
 - hb1arr_7bvq_full_template_nor1_conf2.pdb (PDB file for the initial b1AR
 + cationic norepinephrine complex with CONF2) || -
 hb1arr_7bvq_full_template_nor1.pdb(PDB file for the initial b1AR +
 cationic norepinephrine complex) || -
 hb1arr_7bvq_cterm_model_180003_ala_deletion_nor1_added.pdb (PDB file for
 the initial b1AR + cationic norepinephrine complex with specific model of
 cterm) || - hb1arr_7bvq_cterm_model_180003_ala_deletion_nor1_conf2.pdb
 (PDB file for the initial b1AR + cationic norepinephrine complex with
 conf2) \|- ldock_rpkmin_jd.sh (RosettaLigand repacking shell script to get
 rid of bad contacts in the protein-ligand complex) \|- ldock-rs_jd.sh
 (RosettaLigand test docking shell script) \|-
 generate-ligand-conformers.sh (Code for generate ligand conformers and fa
 and cen folders) \|- ligand (RosettaLigand ligand parameter files) ||- fa
 (full-atom model) ||- cen (centroid model) ||- \_nor1.parm (RosettaLigand
 ligand parameter files) ||- others are intermediate files \|-
 hb1arr_7bvq_full_template_nor1_conf2_t01_50k_ldock-rs.sh (RosettaLigand
 docking of 50K structures SLURM job submission script) \|-
 hb1arr_7bvq_full_template_nor1_conf2-input.pdb (input structure file for
 the RosettaLigand docking after repacking) \|- ligand_dock_tnew1.xml (XML
 file for RosettaLigand docking protocol) \|- get_top50_from_50k_pdb.run
 (Shell script code for getting top 50 of docked structures from the 50K
 output structures) ### Dataset ligand\_dock\_S-Propranolol.zip (repeated
 documents were omitted, RosettaLigand docking of S-Propranolol to beta1AR)
 \|- clean_pdb_builds (Initial files for ligand + receptor complex,
 receptors include C-terminal and ICL3 loops, the major helix part of the
 receptors are based on structures from protein data bank, users can match
 up the files with the source based on the second part of the file name
 (i.e., 3SN6 or 7BVQ)) \|- prs1_ligand (RosettaLigand S-Propranolol ligand
 parameter files) || - fa (full-atom model) || - cen (centroid model) || -
 \_prs1.parm (RosettaLigand S-Propranolol ligand parameter files) ###
 Dataset ligand\_dock\_R-Propranolol.zip (docking of R-Propranolol to beta
 1 AR) \|- clean_pdb_builds (Initial files for ligand + receptor complex,
 receptors include C-terminal and ICL3 loops, the major helix part of the
 receptors are based on structures from protein data bank, users can match
 up the files with the source based on the second part of the file name
 (i.e., 3SN6 or 7BVQ)) \|- ligand (RosettaLigand ligand parameter files) ||
 - fa (full-atom model) || - cen (centroid model) || - \_pro1.parm
 (RosettaLigand R-Propranolol ligand parameter files) ### Dataset
 ligand\_dock\_D-sotalol.zip (RosettaLigand docking of D-sotalol to
 beta1AR) \|- clean_pdb_builds (Initial files for ligand + receptor
 complex, receptors include C-terminal and ICL3 loops, the major helix part
 of the receptors are based on structures from protein data bank, users can
 match up the files with the source based on the second part of the file
 name (i.e., 3SN6 or 7BVQ)) \|- ligand ( ligand parameter files) || - fa
 (full-atom model) || - cen (centroid model) || - \_sotp.parm
 (RosettaLigand d-sotalol ligand parameter files) ### Dataset
 ligand\_dock\_L-sotalol.zip (RosettaLigand docking of L-sotalol to
 beta1AR) \|- clean_pdb_builds (Initial files for ligand + receptor
 complex, receptors include C-terminal and ICL3 loops, the major helix part
 of the receptors are based on structures from protein data bank, users can
 match up the files with the source based on the second part of the file
 name (i.e., 3SN6 or 7BVQ)) \|- ligand RosettaLigand ligand parameter
 files) || - fa (full-atom model) || - cen (centroid model) || -
 \_lstp.parm (RosettaLigand l-sotalol ligand parameter files) ### Dataset
 D\_sotalol\_b1AR.zip (Molecular Dynamics simulation files for beta1AR -
 d-sotalol system) \|- step5_input.parm7 (Amber parameter file for the
 system ) \|- step5_input.pdb (coordinate file for the system in the PDB
 format) \|- step5_input.psf (protein structure file of the system used for
 atom names and connectivity, can be used to visualize dcd trajectory
 files) \|- step5_input.rst7 (coordinate file that can be used as an input
 and restart file for Amber) \|- step6.0_minimization.mdin (Amber
 simulation input file for the minimization step) \|-
 step6.1-6.6_minimization.mdin (Amber simulation input files for the
 equilibration step 6.1 to step 6.5, respectively) \|-
 step7.1_production.mdin (Amber simulation input file for the production
 step 7.1) \|- step7_production.mdin (example Amber simulation input file
 for the rest of the production steps and can be used in the job submitting
 script) \|- step7_production_restraints_CORE_CA_NE.mdin (example Amber
 simulation input file using restraint for the binding pocket and the drug)
 \|- step7_production_restraints_all_CA_NE.mdin (example Amber simulation
 input file using restraint for the protein backbone and the drug) \|-
 step8_production_LiGaMD.mdin (example Amber simulation input file for the
 preparation of Gaussian accelerated MD, GaMD, and can be used in the job
 submitting script) \|- step8_production_LiGaMD2.mdin (example Amber
 simulation input file using GaMD and can be used in the job submitting
 script) \|- slurm_cmd.sh (job submitting script using SLURM for
 conventional MD, cMD, simulation) \|- slurm_GaMD.sh (job submitting script
 using SLURM for Gaussian accelerated MD, GaMD, simulation) \|-
 d_sotalol_b1_cmd.dcd (binary simulation trajectory of cMD for about 1,000
 ns) \|- d_sotalol_b1_GaMd.dcd (binary simulation trajectory of GaMD for
 about 1,000 ns) ### Dataset L\_sotalol\_b1AR.zip (Molecular Dynamics
 simulation files for beta1AR – l-sotalol system, the listed files share
 the same names and guidelines as the d-sotalol simulations.) ### Dataset
 R\_propranolol\_b1AR.zip (Molecular Dynamics simulation files for beta1AR
 – R-propranolol system, the listed files share the same names and
 guidelines as the d-sotalol simulations.) ### Dataset
 S\_propranolol\_b1AR.zip (Molecular Dynamics simulation files for beta1AR
 – S-propranolol system, the listed files share the same names and
 guidelines as the d-sotalol simulations.) ## Sharing/Access information
 Experimental PDB files were downloaded from the Protein Data Bank PDB
 3SN6:
 [https://www.rcsb.org/structure/3sn6](https://www.rcsb.org/structure/3sn6)
 PDB 7BVQ:
 [https://www.rcsb.org/structure/7BVQ](https://www.rcsb.org/structure/7BVQ)
 PDB 7BU6:
 [https://www.rcsb.org/structure/7BU6](https://www.rcsb.org/structure/7BU6)
 ## Code/Software TM4-TM6-distance.tcl (VMD Tcl/Tk code for analyze the
 distance between TM4 and TM6) contact-AA-ligand.tcl (VMD Tcl/Tk code for
 analyze the contact amino acid residues)