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01-system_files

README.md

Protein-Ligand System

For this tutorial we will look at the binding of the ligand below to the protein Cyclophilin D.

The protein-ligand system looks like this

Prepare protein and ligand files

The following commands to prepare the protein and ligand files are stored in 01-prepare-files.sh (run bash 01-prepare.sh on the terminal).

First, we need to prepare the ligand files. Run the following in a terminal to generate a MOL2 file with GAFF2 atom types and AM1BCC charges

antechamber -fi pdb -fo mol2 -i ligand.pdb -o ligand.am1bcc.gaff2.mol2 -at gaff2 -c bcc -rn LIG -pf y

Next, we generate a frcmod file to add any missing bonded parameters.

parmchk2 -f mol2 -i ligand.am1bcc.gaff2.mol2 -s gaff2 -o ligand.frcmod

For the protein, we will need to remove any hydrogen atoms otherwise tleap will complain about atom names not recognized in AMBER.

pdb4amber --nohyd protein.pdb > protein.noH.pdb

Combine protein and ligand to a single file

Now that we have a prepared protein and ligand PDB files, we can combine these two with OpenMM modules to get a single PDB file (run python 02-combine_protein-ligand.py on the terminal).

from openmm.app import PDBFile, Modeller

protein = PDBFile("protein.noH.pdb")
ligand = PDBFile("ligand.pdb")

protein_ligand = Modeller(protein.topology, protein.positions)
protein_ligand.add(ligand.topology, ligand.positions)

with open("protein_ligand.pdb", "w") as f:
    PDBFile.writeFile(
        protein_ligand.topology,
        protein_ligand.positions,
        f,
    )

Build AMBER Topologies

Next, we will use the TLeap API from pAPRika to build the AMBER files. We will build AMBER files for the ligand and protein-ligand system with the mbondi2 radii (used in OBC2 implicit solvent model). For the protein we will use the ff19SB force field model. The python code below creates the AMBER files (run python 03-create_system.py on the terminal).

from paprika.build.system import TLeap

# Build AMBER Topologies for Ligand
system = TLeap()
system.output_prefix = "ligand-ff19SB"
system.neutralize = False
system.pbc_type = None
system.template_lines = [
    "set default PBRadii mbondi2",
    "source leaprc.gaff2",
    "loadamberparams ligand.frcmod",
    "LIG = loadmol2 ligand.am1bcc.gaff2.mol2",
    "model = loadpdb ligand.pdb",
]
system.build(clean_files=False)
# Do HMR so we can increase integration time step
system.repartition_hydrogen_mass()

# Build AMBER Topologies for Protein-Ligand system
system = TLeap()
system.output_prefix = "protein-ligand-ff19SB"
system.neutralize = False
system.pbc_type = None
system.template_lines = [
    "set default PBRadii mbondi2",
    "source leaprc.protein.ff19SB",
    "source leaprc.water.opc",
    "source leaprc.gaff2",
    "loadamberparams ligand.frcmod",
    "LIG = loadmol2 ligand.am1bcc.gaff2.mol2",
    "model = loadpdb protein_ligand.pdb",
]
system.build(clean_files=False)
# Do HMR so we can increase integration time step
system.repartition_hydrogen_mass()