exercise docking

8/12/2019 Exercise Docking

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Exercise: Docking using MOEOliver Taboureau, [email protected]

The purpose of this exercise is, based on the pharmacophore and the virtual screeningof last week, to dock a set of compounds into a protein, a leucine transporter

(2A65.pdb) and analyze the output results from MOE

The dataset contains 5 serotonin receptors inhibitors potentially binding to the leucine

transporter.

! Click on an xterm on the panel below. That will open a newwindow.

!

ssh –X [email protected] ! ssh –X life

! All the files you will need are on your student account in“Exercise_03.11”

! Go to this directory by typing “cd Exercise_03.11”, then you canstart the program MOE by typing “moe”

Upload the dataset with the 5 hits:

File"

Open"

5_seroto.mdb

Upload the protein:

File" Open" 2A65.pdb (the window “Load PDB File” will pop up, click OK) (In

MOE not in Database Viewer)

You can color the chains for a better visualization:

Render" Color" Chain

Then, open the sequence editor

Window" Sequence Editor

Question 1: How many chains do you have and what is described on each of them?

What is BOG? (Look on the 2A65.pdb file with a text editor for help)

The water molecules and sugar are not needed for the exercise. So, we will delete

them.

Right-click on chain 3, select “Delete selected chain” and click OK

Right-click on BOG and select “Delete”. Repeat the procedure for all BOG.



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Now, we want to have a look on how the ligand (LEU) binds to the protein and what

parts of the ligand contribute to different interactions with proteins.

First, we have to select the ligand LEU.

In the Sequence Editor, click on the LEU residue in chain 2. Then go to

“Selection" Atoms" of selected residues.

Then, in the main window:

Compute" Surface and Maps

In the field “near”, choose “Selected Atoms”

In Color, change “Solid” to “Line”

Click “Apply”

Hide the residues of the proteins:

Render" Hide" All

Then, in the sequence editor, right-click on the ligand LEU and go to

Atoms" Show

This will bring the ligand LEU on screen.

You can also display the protein in a schematic view.

Right-click on the chain 1

Backbone" Line

Question 2: From the surface, describe the ligand atoms that are part of H-bonding,

hydrophobic and mild polar interactions.

We will integrate the LEU ligand in the 5_seroto.mdb file

In the Sequence Editor, right-click on the ligand LEU (in chain 2) and choose

Atoms" Select

Then, go to the database viewer, click on

Entry" Add Entry

In selection, change “Ignore” to “Selected Atoms”, include a name in mol_name andan integer in -logIC50 (for example “Leu” and “5”). Click “OK”



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Now, we can delete the ligand and prepare the protein for docking.

In the Sequence Editor, right-click on the ligand LEU (in chain 2) and select “Delete”.

It is possible that some hydrogens are missing.

In the main window, go to

Edit" Hydrogens" Add hydrogens

Then prepare the protein and minimize the position of atoms.

In the main window, go to

Compute" Protonate 3d and click OK (run-time ~ 5 min)

When the protonation of the protein is done, you can incorporate back the ligand LEU

into the binding pocket.

In the database viewer, double-click on the field “mol” of the LEU and click OK.

Finally we can dock the list of compounds.

Go to Compute" Simulations" Dock

In the Dock window, in the field ligand select “MDB file” and browse to the file

5_seroto.mdb.

In “retain”, select only 10 (this is the number of poses with the best score for each

compound docked) and click OK.

After 5 min you should get a file (dock.mdb) with all the poses for all the compounds

docked in the protein.

Question 3: How many fields do you have and what do they mean? (Look in the

docking.pdf file for help on the definitions)

In the database viewer go to

Compute" Sort and in select S (S_Score). Click OK.

Question 4: Which are the first, the second and the third hits?

Finally, you can see the interactions between the ligand and the protein.

To see the protein-ligand interactions of the ligand LEU, go to

Compute" ligand-interactions (in Moe)

A graphical viewer will appear.



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Question 5: With which residues does the ligand interact with?

If you have time and curiosity ,you can do the same with the hits 2 and 3. For that,,

double-click on the « mol» field of the molécule of interest in the database viewer to

include the hit into the protein. Then, in the Sequence Editor click on « chain 3 » and

in the ligand-interaction GUI change « ligand atoms » to « selected chain » and clickon « Apply »

Question 6: Do you see similar interactions as those with the LEU substrate?

exercise docking

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