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CADD course learning (7) -- Simulation of target and small molecule interaction (semi flexible docking autodock)
2022-07-05 20:36:00 【Stunned flounder (】
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
- install Python Running environment , And set environment variables
- 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 - Mgltool**,exe(windows edition ): Just like installing an ordinary program, double-click to install .
Docking cases
AutoDock Docking system :PDB 1IEP
AutoDock Docking steps :
- Prepare ligand and receptor files (AutoDockTools)
- Prepare grid file (AutoGrid)
- 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 :
- 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; - 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 ; - 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 :
- Energy analysis
- Clustering analysis
- And X-ray Crystal conformation comparison
- 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 ;
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