Protein Ligand Docking

0. Generate ligand topology

Prerequisites:

1. Ligand coordinates in XYZ file
2. Openbabel: sudo apt install obabel
3. Antechamber
4. Acpype

Step 1: Convert .xyz coodinates to .mol2

obabel -ixyz LIGX.xyz -omol2 -OLIGX.mol2

Step 2: Run Acpype to generate topology

acpype -i LIGX.mol2

1. Generate protein starting structure and topology

Prerequisites: charmm36-feb2021.ff

gmx pdb2gmx -f protein.pdb -o 1-pdb2gmx.gro -ff charmm36-feb2021 -water tip3p 2>&1 | tee 1-pdb2gmx.log

2. Combine structures and topologies

Follow the sections titled "Build the Complex" and "Build the Topology" described here. Make sure the filename of the complex is 2-complex.gro.

3. Generate bounding box

gmx editconf -f 2-complex.gro -o 3-newbox.gro -bt dodecahedron -d 1.0 2>&1 | tee 3-newbox.log

4. Solvate

gmx solvate -cp 3-newbox.gro -cs spc216.gro -p topol.top -o 4-solvated.gro 2>&1 | tee 4-solvate.log

5. Preprocess

Download ions-PME.mdp from here.

gmx grompp -f ions-PME.mdp -c 4-solvated.gro -p topol.top -o 5-solvated.tpr -maxwarn 1 2>&1 | tee 5-grompp.log

6. Neutralize

gmx genion -s 5-solvated.tpr -o 6-neutralized.gro -p topol.top -pname NA -nname CL -neutral << 2>&1 | tee 6-neutralize.log

Select the SOL group (15) at the prompt.

7. Preprocess

Download em.mdp from here.

gmx grompp -f em.mdp -c 6-neutralized.gro -p topol.top -o 7-neutralized.tpr 2>&1 | tee 7-grompp.log

8. Energy Minimization

gmx mdrun -deffnm 7-neutralized -v -c 8-minimized.gro 2>&1 | tee 8-minimization.log

9. Plot Potential vs Timestep

• Get GNUplot: sudo apt install gnuplot
• If that doesn't work, try: sudo apt install gnuplot-x11
• Download 9-minimization-potential.p

Extract potential data from EDR file:

gmx energy -f 7-neutralized.edr -o 9-minimized-potential.xvg 2>&1 | tee 16-energy.log

Select potential at the prompt. Plot using gnuplot:

gnuplot 9-minimization-potential.p

10. Create an index for the ligand

gmx make_ndx -f LIGX.gro -o index_LIGX.ndx 2>&1 | tee 10-index.log

Enter the following at the prompt to select all ligand atoms other than hydrogens:

0 & ! a H*
q

11. Generate position restraints for ligand

gmx genrestr -f LIGX.gro -n index_LIGX.ndx -o posre_LIGX.itp -fc 1000 1000 1000 2>&1 | tee 11-genrestr.log

Select the ligand (3) at the prompt.

12. Include the position restraints in the system topology

Follow the section titled Restraining the Ligand from here.

13. Create an index for the system

gmx make_ndx -f 8-minimized.gro -o index.ndx 2>&1 | tee 13-index.log

Enter the following at the prompt to group the protein and the ligand:

1 | 13
q

14. Preprocess for NVT

Download nvt.mdp.

gmx grompp -f nvt.mdp -c 8-minimized.gro -r 8-minimized.gro -p topol.top -n index.ndx -o 14-nvt.tpr 2>&1 | tee 14-grompp.log

15. NVT Run

gmx mdrun -deffnm 14-nvt -v -c 15-nvt.gro 2>&1 | tee 15-nvt.log

16. Plot Temperature from NVT

• Download 16-nvt-temperature.p Extract temperature data from EDR file:

gmx energy -f 14-nvt.edr -o 16-nvt-temperature.xvg 2>&1 | tee 16-energy.log

Select temperature at the prompt. Plot using gnuplot:

gnuplot 16-nvt-temperature.p

17. Preprocess for NPT

Download npt.mdp.

gmx grompp -f npt.mdp -c 15-nvt.gro -t 14-nvt.cpt -r 15-nvt.gro -p topol.top -n index.ndx -o 17-npt.tpr 2>&1 | tee 17-grompp.log

18. NPT Run

gmx mdrun -deffnm 17-npt -v -c 18-npt.gro 2>&1 | tee 18-npt.log

19. Plot Pressure from NPT

• Download 19-npt-pressure.p Extract pressure data from EDR file:

gmx energy -f 17-npt.edr -o 19-npt-pressure.xvg 2>&1 | tee 19-energy-pressure.log

Select pressure at the prompt. Plot using gnuplot:

gnuplot 19-nvt-pressure.p

20. Plot Density from NPT

• Download 20-npt-density.p Extract density data from EDR file:

mpirun -np 1 gmx_mpi energy -f 17-npt.edr -o 20-npt-density.xvg 2>&1 | tee 20-energy-density.log

Select density at the prompt. Plot using gnuplot:

gnuplot 20-nvt-density.p

21. Preprocess for MD

Download md.mdp.

gmx grompp -f md.mdp -c 18-npt.gro -t 17-npt.cpt -r 18-npt.gro -p topol.top -n index.ndx -o 21-md.tpr 2>&1 | tee 21-grompp.log

22. MD Run

gmx mdrun -deffnm 21-md -v -c 22-md.gro 2>&1 | tee 22-md.log