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Tutorial Molecular Docking Using ArgusLab (4ACM)

Prof. Dr. Walter Filgueira de Azevedo Jr. [email protected]

azevedolab.net 1

Introduction

Docking with ArgusLab In this tutorial you will learn how to carry out docking simulation using the ArgusLab (Joy et al., 2006) docking program. This docking software is freely available at www.arguslab.com. We used the atomic coordinates of cyclin-dependente kinase 2 in comples with 3-amino-6-(4-{[2-(dimethylamino)ethyl]sulfamoyl}phenyl)- n-pyridin-3ylpyrazine-2-carboxamide (PDB access code: 4ACM.) (Berg et al., 2012).

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Loading PDB file

To open a PDB file click: File>Open..., as show below.

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Loading PDB file

Then browse the folder where you have the PDB file.

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Loading PDB file

You will have the structure in the graphical screen. On the left, you have the Tree View tool. Click on the “+” to expand the tree.

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Selecting ligand

Expand the Tree View of 4ACM and open up the Residues/Misc. folder to show the ligands.

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Selecting ligand

You should have something like this. The active ligand in “1302 7YG”, which will be used in the docking simulations.

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Selecting ligand

Left click on “1302 7YG” in the Tree View to select the active ligand. It should appear in yellow.

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Selecting ligand

Now click on Edit>Hide Unselected, as shown below. You will have only the active ligand on the screen.

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Selecting ligand

To center the ligand click here.

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Adding hydrogens

To add hydrogens to the ligand hold down the shift key and click here.

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Adding hydrogens

Here we have the ligand with hydrogens added to the structure.

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Making groups

Here we have the ligand with hydrogens added to the structure. Right click on “1302 7YG” on the Tree View and select “Make a Ligand Group from This Residues” option.

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Making groups

Expand Groups folder in the Tree View.

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Making groups

Now we have access to the ligand in the Groups folder.

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Making groups

Left-click on “17YG” in the Groups folder to select the atoms of the ligand on the screen. Copy (Ctrl+C) and paste (Ctrl+V) the selected ligand.

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Making groups

Expand the Misc. folder and you will see the copy of the ligand named “2184 7YG”.

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Making groups

Right click on “2184 7YG” on the Tree View and select “Make a Ligand Group from This Residues” option, as shown below.

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Making groups

Now we have two ligands in the Groups folder named “1 7YG” and “2 7YG”. Now we have to rename these ligands to “ligand-xray” and “ligand”, respectively.

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Renaming groups

Right-click on “1 7YG” in the Groups foder and select “Modify group...” option, as shown below.

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Renaming groups

In the “Modify group...” Dialog box, type in the “ligand-xray”. Don’t change the Groups type.

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Renaming groups

Do the same to the “2 7YG” and rename to “ligand”.

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Changing ligand view

Right-click on the ligand and and select “Set Render Mode” and choose “Cylinder med” option, as shown below.

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Changing ligand view

You will have the following view.

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Making binding site

Right-click on the ligand-xray in the Groups folder and choose “Make a BindingSite Group for this Group”, as shown below.

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Making binding site

Now we have the binding site as show below. Center the molecules by clicking here.

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Docking a ligand

Click on Calculation>Dock a Ligand...

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Docking a ligand

We have the dialog box to enter docking parameters.

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Docking a ligand

Select “4ACM: ligand” on Ligand drop box, as shown below. Then press “Calculate Size” button.

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Docking a ligand

Press the “Advanced...” button.

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Docking a ligand

Change “Max. number of poses” to 500.

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Docking a ligand

Press “OK” button.

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Docking a ligand

Press “Start” button to initiate docking simulation.

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Docking a ligand

After few seconds you will see the message “Docking run: elapsed time...”

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Analyzing docking results

In the Tree View tool, select ligand and ligand-xray by holding down the “Ctrl” key and left-clicking on both groups. You will have the following screen.

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Analyzing docking results

Righ-click on the “Groups” folder tab in the Tree View and select “Calc RMSD position between two similar Groups”, as shown below.

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Analyzing docking results

We have the docking RMSD between crystallographic position and pose.

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Analyzing docking results

Click on File>Save as..., as shown below.

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Analyzing docking results

Then choose ArgusLab Files (*.agl).

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Analyzing docking results

Save your results as a PDB file.

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Analyzing docking results

Save your results as a PDB file.

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Analyzing docking results

In the Tree View expand Calculations folder

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Analyzing docking results

Right-click on “ArgusDock...” and select “Save to file...”.

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Analyzing docking results

Select the folder to save the docking results file.

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Docking a ligand (Lamarckian genetic algorithm)

Alternative docking protocol using Lamarckian genetic algorithmis available in the ArgusLab.

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Colophon

This tutorial was produced in a DELL Inspiron notebook with 6GB of memory, a 700 GB hard disk, and an Intel® Core® i5-3337U CPU @ 1.80 GHz running Windows 8.1. Text and layout were generated using PowerPoint 2013 and figures were captured from ArgusLab program. This tutorial uses Arial font.

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Author

I graduated in Physics (BSc in Physics) at University of Sao Paulo (USP) in 1990. I completed a Master Degree in Applied Physics also at USP (1992), working under supervision of Prof. Yvonne P. Mascarenhas, the founder of crystallography in Brazil. My dissertation was about X-ray crystallography applied to organometallics compounds (De Azevedo Jr. et al.,1995). During my PhD I worked under supervision of Prof. Sung-Hou Kim (University of California, Berkeley. Department of Chemistry), on a split PhD program with a fellowship from Brazilian Research Council (CNPq)(1993-1996). My PhD was about the crystallographic structure of CDK2 (Cyclin-Dependent Kinase 2) (De Azevedo Jr. et al., 1996). In 1996, I returned to Brazil. In April 1997, I finished my PhD and moved to Sao Jose do Rio Preto (SP, Brazil) (UNESP) and worked there from 1997 to 2005. In 1997, I started the Laboratory of Biomolecular SystemsDepartment of Physics-UNESP - São Paulo State University. In 2005, I moved to Porto Alegre/RS (Brazil), where I am now. My current position is coordinator of the Laboratory of Computational Systems Biology at Pontifical Catholic University of Rio Grande do Sul (PUCRS). My research interests are focused on application of computer simulations to analyze protein-ligand interactions. I'm also interested in the development of biological inspired computing and machine learning algorithms. We apply these algorithms to molecular docking simulations, proteinligand interactions and other scientific and technological problems. I published over 160 scientific papers about protein structures and computer simulation methods applied to the study of biological systems (H-index: 33). These publications have over 3700 citations. I am editor for the following journals:

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References

Berg S, Bergh M, Hellberg S, Högdin K, Lo-Alfredsson Y, Söderman P, von Berg S, Weigelt T, Ormö M, Xue Y, Tucker J, Neelissen J, Jerning E, Nilsson Y, Bhat R. Discovery of novel potent and highly selective glycogen synthase kinase-3ß (GSK3ß) inhibitors for Alzheimer's disease: design, synthesis, and characterization of pyrazines. J Med Chem. 2012; 55(21):9107-19. Joy S, Nair PS, Hariharan R, Pillai MR. Detailed comparison of the protein-ligand docking efficiencies of GOLD, a commercial package and ArgusLab, a licensable freeware. In Silico Biol. 2006;6(6):601-5. Last update on July 3rd 2016

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