SI2009 Virtual Screening Rescoring and Refinement Using AutoDock2MMGBSA

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Instructor Dong Xu, Postdoctoral Fellow, NBCR/McCammon Group, UCSD

Note:

Bold lines"" are the commands you need to run in this tutorial session!
Most of the commands in section will be executed on kryptonite
Please copy/paste them to your terminal window in order to avoid input errors

Contents

Setup Working Environment on Kryptonite Cluster

Open a terminal window and type:

ssh your_user_name@ieng6-203.ucsd.edu
ssh kryptonite.nbcr.net
source /nas2/scratch/dxu/SI2009/setup.bash

AutoDock2MMGBSA (A2M) Rescoring

In this demo, we will use A2M to rescore AutoDock Vina predicted binding poses and see how A2M rescoring helps capture the correct binding mode.

We use the crystal structure of Influenza Neuraminidase N9 (A/TERN/AUSTRALIA/G70C/75) bound with a small inhibitor DANA as an example.

Files

See what files you have:

ls -l
RCSB Receptor/Ligand Complex: 2QWC.PDB
Receptor: 2qwc-protein.pdb
Ligand: 2qwc-ligand.mol2
Vina config file: vina.conf
Vina SGE script: vina.sge
A2M SGE script: a2m.sge
Vina Docking

We now use vina to dock the crystal ligand back to the receptor.

qsub vina.sge

This job will take < 5 minutes.

Check job status

qstat -u your_user_name
Analyze Docking Results

Open vina.log to see the docking energies.

less vina.log

Compare the RMSD between docked poses and crystal ligand

ls *_all_ligand_*.pdbqt|xargs -ti sh -c 'echo {}; ~dxu/bin/rmsd.csh lig.pdbqt {}' >> rmsd
less rmsd

Can you tell which is the best pose? Did Vina give the correct prediction?

A2M Rescoring

We now run A2M to rescore all the poses.

qsub a2m.sge

This job will take ~25-30 minutes, meaning you have time for a coffee break! Or you can proceed to the next section.

Check job status

qstat -u your_user_name

If the job is running, take a look at A2M log file

less 2qwc-protein_2qwc-ligand_all_ligand_1/A2M*.log
Visualize Docking Results

It's a bit hassle to transfer files from kryptonite to your computer. Open another terminal window:

ssh your_user_name@ieng6-203.ucsd.edu
scp kryptonite.nbcr.net:~/data/A2M/*-ligand_all.pdb .
scp kryptonite.nbcr.net:~/data/A2M/2QWC.PDB .
exit
bash
cd ~/Desktop
scp your_user_name@ieng6-203.ucsd.edu:~/*-ligand_all.pdb .
scp your_user_name@ieng6-203.ucsd.edu:~/2QWC.PDB .

On your local Mac, go to Finder --> Go --> Applications --> VMD 1.8.6

Load the 2QWC PDB structure into VMD, In the VMD Main window,

File --> New Molecule --> Filename --> Browse --> 2QWC.PDB --> Load
Graphics --> Representations --> replace "all" with "protein" --> Drawing Method: New Cartoon
Graphics --> Representations --> Create Rep --> replace "protein" with "resname DAN and noh" --> Drawing Method: Licorice
File --> New Molecule --> Filename --> Browse --> 2qwc-protein_2qwc-ligand_all.pdb --> Load
Graphics --> Representations --> replace "all" with "noh" --> Drawing Method: Licorice --> Material: BrushedMetal

In VMD main window, click the left button located in the lower right corner to go through all the docked conformations. Do you see the best binding mode?

Analyze A2M Results

Go back to the first terminal window, Check the job status

qstat -u your_user_name

After the job is finished, let's extract and sort A2M energies.

~dxu/bin/extract_a2m_results.sh

and open the output file:

less a2m_gbtot.sorted

If you can't wait for the job to finish, I have the file already prepared in /nas2/scratch/dxu/SI2009/Results

less /nas2/scratch/dxu/SI2009/Results/a2m_gbtot.sorted

The first line give you the lowest energy pose, does it match the best pose from RMSD analysis?


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