CADD course learning (7) -- Simulation of target and small molecule interaction (semi flexible docking autodock)

CADD Course study （7）-- Simulate the interaction between the target and small molecules （AutoDock）

Concept ：
Molecular docking is through the study of the interaction between ligand small molecules and receptor biological macromolecules , Predict its affinity , An important method to realize structure based drug design .

Theoretical basis ：
The original idea of molecular docking originated from Fisher E Proposed “ Lock and key model ”, That is, the first condition for the mutual recognition of receptors and ligands is the matching of spatial structure .

Molecular docking principle
According to geometric matching and energy matching , Find the best interaction mode between two molecules

Receptor: enzyme, ion channel, antibody……
Ligand: drug, peptide, antigen, polysaccharide…
Receptor-Ligand Interactions:
electrostatic interaction, hydrogen bond, hydrophobic interaction

Docking software

• Different systems have different results ;
• DS（LigandFit）,SYBYL（flexx,surflex）,AutoDock The results are not much different
• Autodock Good performance , And open source for free , Safe to use
  Test set ：1300 protein-ligands complexes from PDBbind database

The general process of molecular docking

principle ： When the ligand binds to the receptor , There is electrostatic interaction with each other 、 Hydrogen bond interaction 、 Van der Waals force interaction and hydrophobic force . The binding of ligand and receptor must meet the principle of mutual matching , That is, the geometry of ligand and receptor is complementary 、 Electrostatic interaction complementary matching 、 Hydrogen bond interaction complementary matching 、 Hydrophobic interactions complement each other .

classification

• Rigid butt joint ： During docking , The conformation of the study system does not change . Suitable for investigating relatively large systems , Such as the docking between proteins and between proteins and nucleic acids .
• Semi flexible docking ： During docking , The conformation of the studied system, especially the ligand, is allowed to change within a certain range . It is suitable for docking between macromolecules and small molecules .
• Flexible docking ： During docking , The conformation of the research system is basically free to change . It is generally used to accurately consider the recognition between molecules , Because the conformation of the system can change during the calculation , So the calculation cost the most .
  

AutoDock： Small molecule compounds - Protein docking software

http://autodock.scripps.edu

install

1. install Python Running environment , And set environment variables
2. Autodock***,exe（windows edition ） Double clicking will decompress three files ：autodock4.exe、autogrid4.exe and cygwin1.dl, And automatically copy them to C:\Windows\System32\ Under the folder , installation is complete . then ,DOS You can directly enter “autodock4” or
   “autogrid4” function . For example, manually copy the above three files to other directories , Each time you call this command, you need to point out the path of the storage directory
3. Mgltool**,exe（windows edition ）： Just like installing an ordinary program, double-click to install .
   
   
   

Docking cases

AutoDock Docking system ：PDB 1IEP
AutoDock Docking steps ：

1. Prepare ligand and receptor files （AutoDockTools）
2. Prepare grid file （AutoGrid）
3. Molecular docking calculations （AutoDock）
   

1. Prepare ligand receptor file （AutoDockTools）
（1）Pymo download 11EP, Delete B chain , Remove water molecules ,CL ion
（2） Select the protein part （ Does not contain ligands STI）, Save as 1EP_protein.pdb
（3） Select ligand （STI）, Save as lmatinib.pdb notes ：PDB 1IEP The ligands of ST That is to say lmatinib











If the interface cannot RUN, You can use the command line ：.\autogrid4.exe -p .\dock.gpf





If not RUN, Using the command line .\autodock4.exe -p .\dock.dpf

Summary of semi flexible docking

AutoDock Docking system ：PDB 1lEP AutoDock Half docking steps ：

1. Prepare ligand and receptor files （AutoDockTools）
   Autodock Tools Ligand file preparation ：
   ① Add H atom 、 Add gasteiger Empirical charge 、 Combine nonpolar hydrogen
   ② Set the rotatable key ;
   ③ preservation lig.pdbqt;
   Autodock Tools Receptor document preparation ：
   ① Delete water 、 Add H atom 、 Add gasteiger Empirical charge 、 Merge non
   ② preservation rec.pdbqt;
2. Prepare grid file （AutoGrid）
   ① Selective rigid receptor ;
   ② Set the probe atom type 、 Set the size and position of the box ;
   ③ preservation dock.gpf Parameter control file
   ④ function AutoGrid Program calculation grid ;
3. Molecular docking calculations （AutoDock）
   ① Choose rigid receptors and flexible ligands ;
   ② Set the number of output conformations of genetic algorithm conformation search ;
   ③ preservation dock.dpf Parameter control file
   ④ function AutoDock Program docking , Output dock.dlg;

AutoDock Docking system ： PDB 1IEP

AutoDock Analysis and evaluation of docking results ：

1. Energy analysis
2. Clustering analysis
3. And X-ray Crystal conformation comparison
4. Choice of optimal binding conformation
   
   
   

The molecular conformations and complexes of docking ligands are derived

• Click on “Buld current” Two docking conformations can be superimposed for comparison ;
• Click on “Build Al" All ligand conformations can be superimposed （ If the number is large, don't try ）;
• Click on “Play Parameters” You can set the playback frame rate 、 Start frame 、 End frame, etc
• Click on “Write current” Save the currently displayed docking ligand conformation ; Click on Write Complex Save the currently displayed docking receptor - Ligand complex conformation .
  
  
  

stay PyMol see

summary （ Selection principle of optimal binding conformation ）

Choice of optimal binding conformation

• Take the measured crystal structure as a reference ;（ If there are receptor ligand binding crystals ）
• Choose the one with high affinity in the active pocket ;
• Choose the one where clustering is dominant ;
• Recipient - Ligand noncovalent interaction analysis （ Combined with the literature, judge and screen the appropriate conformation ）
• Fully flexible docking to obtain a better conformation ;
• The result of semi flexible docking （ compound ） Conduct molecular dynamics simulation to achieve steady state , Docking again in a steady-state conformation ;