Difference between revisions of "DOCKovalent linker design tutoral"

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Line 10: Line 10:
 
==Step 1. Custom Ligand and Library Generation ==
 
==Step 1. Custom Ligand and Library Generation ==
 
1/Custom Ligand / Library Generation
 
1/Custom Ligand / Library Generation
 +
 
  cd 1-Custom-Ligand-Library-Generation
 
  cd 1-Custom-Ligand-Library-Generation
 +
 
For meta-SF library building
 
For meta-SF library building
  
reaction1:
+
reaction1: scaffod.smi is the smile of the scaffold for reaction
 +
817.zinc.list.smi is the smile of collect 817 different diamine linkers
  
 
  python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi
 
  python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi
                        scaffod.smi is the smile of the scaffold for reaction
+
                     
                        817.zinc.list.smi is the smile of collecte 817 different diamine linkers
+
 
reaction2:
 
reaction2:
 
  python step2-reaction-SF-meta.py scaffold.ism
 
  python step2-reaction-SF-meta.py scaffold.ism
 +
 
                         inputfile: scaffold.ism is the primary products without the SF
 
                         inputfile: scaffold.ism is the primary products without the SF
 
                         outputfile: final_scaffold1.smi
 
                         outputfile: final_scaffold1.smi
 +
 
reaction3:  remove the doubles
 
reaction3:  remove the doubles
 
  python step3-remove_doubles.py final_scaffold1.smi
 
  python step3-remove_doubles.py final_scaffold1.smi
Line 39: Line 43:
 
  echo "5K9I-B-X44      B      295">>lys.list
 
  echo "5K9I-B-X44      B      295">>lys.list
 
  bash step0_prepare_build_system.sh  5K9I-B-X44
 
  bash step0_prepare_build_system.sh  5K9I-B-X44
in the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
+
In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb
 
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
 
Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom
 
  bash step1_run_build_system.sh 5K9I-B-X44  
 
  bash step1_run_build_system.sh 5K9I-B-X44  
Line 52: Line 56:
 
  bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
 
  bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)
 
box_margin is defined from the center of the xtal-lig.pdb file
 
box_margin is defined from the center of the xtal-lig.pdb file
 +
 +
==modify the INDOCK parameters for saving multiple poses ==
 +
 +
cd 3-modify-the-INDOCK-parameters
 +
change the default parameters for covalent docking
 +
 +
  bump_maximum                  100
 +
  bump_rigid                    100
 +
  number_save                  1000
 +
  number_write                  1000
 +
  molecules_maximum            100000
 +
  bond_len                      1.61
 +
  bond_ang1                    121.02
 +
  bond_ang2                    107.36
 +
  len_range                    0.0
 +
  len_step                      0.1
 +
  ang1_range                    20.0
 +
  ang2_range                    20.0
 +
  ang1_step                    5
 +
  ang2_step                    5
 +
  check_clashes                no
 +
  per_atom_scores              yes

Revision as of 09:34, 4 April 2018

This was written on April 4, 2018.

This tutorial is for designing linkers for a covalent inhibitor and is supplement the work in preparation (Wan et al 2018).


These file are in the /mnt/nfs/home/xiaobo/UCSF_scripts/2018-4-3-covlanet_lysine_wiki-tutorial


Step 1. Custom Ligand and Library Generation

1/Custom Ligand / Library Generation

cd 1-Custom-Ligand-Library-Generation

For meta-SF library building

reaction1: scaffod.smi is the smile of the scaffold for reaction 817.zinc.list.smi is the smile of collect 817 different diamine linkers

python step1-reaction-amines-Br.py scaffod.smi 817.zinc.list.smi
                      

reaction2:

python step2-reaction-SF-meta.py scaffold.ism
                       inputfile: scaffold.ism is the primary products without the SF
                       outputfile: final_scaffold1.smi

reaction3: remove the doubles

python step3-remove_doubles.py final_scaffold1.smi
                       inputfile:final_scaffold1.smi
                       outputfile: no_doubles_out.ism

The no_double_out.ism was used to generate db2 file for covalent docking log into gimel

setenv DOCKBASE /nfs/soft/dock/versions/dock37/DOCK-3.7-beta9-min
setenv DOCKBASE /mnt/nfs/home/xiaobo/combine_docknormal_dock_covalent_3.7_and_tart/DOCK_from_githup_2016_5_27
/nfs/soft/tools/utils/qsub-slice/qsub-mr-meta -tc 50 --map-instance-script "/nfs/soft/tools/utils/qsub-slice/qsub-mr-map.sh" -s $BUILD_ENVIRONMENT -l 1 no_doubles_out.ism $DOCKBASE/ligand/generate/build_database_ligand.sh --no-db --no-solv --no-mol2 --single --covalent

Step 2 Protein preparation (different lysine rotamers)

2/Protein preparation (different lysine rotamers)

cd 2-Protein-preparation-different-lysine-rotamers

find the modification lys number in the PDB

echo "5K9I-B-X44      B       295">>lys.list
bash step0_prepare_build_system.sh  5K9I-B-X44

In the window of chimera, select all of the 27 lysine rotamers and click the button of OK. Reselect all the lysine rotamers in the PDB structure, and the save to PDB format LYS-5K9I-B-X44.pdb Then, to generate all 28 structure folds, and then automatically calculate the steric clash with nearby residues, and select the rotamer with no steric clashes. This scripts will also calculate the nearest atom of in the compound to the lysine NZ atom

bash step1_run_build_system.sh 5K9I-B-X44 
5K9E-B-X44      SBH     2.038
5K9B-B-X44      SBH     2.321
5K9I-B-X44      OBI     2.949
5K9L-B-X44      SBH     4.683
5K9R-B-X44      OBI     4.925

Each folder contains rec.pdb and xtal-lig.pdb

For each folder

bash step1_DOCKINV.blastermaster.sh 5K9I-B-X44 box_margin(10) 1(covalent docking)

box_margin is defined from the center of the xtal-lig.pdb file

modify the INDOCK parameters for saving multiple poses

cd 3-modify-the-INDOCK-parameters change the default parameters for covalent docking

 bump_maximum                  100
 bump_rigid                    100
 number_save                   1000
 number_write                  1000
 molecules_maximum             100000
 bond_len                      1.61
 bond_ang1                     121.02
 bond_ang2                     107.36
 len_range                     0.0
 len_step                      0.1
 ang1_range                    20.0
 ang2_range                    20.0
 ang1_step                     5
 ang2_step                     5
 check_clashes                 no
 per_atom_scores               yes