PLIpp - Protein Ligand Interactions python project

This python project aims to predict the Interaction between protein and ligand based on their coordinates using only Pandas, Numpy, and Scipy library. This is my Python project from semester 1, Master 1 In silico Drug Design at Université Paris Cité, France

References

Adasme, M. et al. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucl. Acids Res. (05 May 2021), gkab294. doi: 10.1093/nar/gkab294

Requirements

This code was tested in Python 3.12.8.

git clone https://github.com/caominhtr/PLIpp.git
cd PLIpp
conda env create -f PLIpp-env.yml
conda activate PLIpp-env

Running PLIpp

To generate interactions between a protein and a ligand using the PLIproject, the following steps should be followed:

Step 1: Assign hydrogen atoms

My suggestion is to use free software ChimeraX with Add Hydrogen option:

Step 2: Fix errors in pdb file (if any)

To find any errors in pdb file, use:

python3 extractfile.py 6xjk.pdb
python3 extractfile.py 3dy7.pdb 

The most common error with the pdb file is the white space between some columns, for example:

If there are errors, manually fix it before running PLIpp

Step 3: Find residues in the binding site

To find residues involved in the interactions with the ligand, use:

python3 bindingsite.py 6xjk.pdb
python3 bindingsite.py 3dy7.pdb 

The output is in csv file format named: "_protein_activesite.csv"

Step 4: Find a ligand pharmacophore

To find the ligand pharmacophore, use:

python3 pharmacophore.py 6xjk.pdb
python3 pharmacophore.py 3dy7.pdb

The output is in csv file format named:"_pharmacophore.csv"

Interpretation

Here are some geometric conditions for interactions between protein and ligands:

π-π interaction

• PLIpp only takes into account of 6-membered aromatic rings
• Aromatic residues: Phe, Tyr, Trp
• π-π sandwich stacking: two rings are parallel and the distance between two centers is less than 5.5Å
• π-π T-shaped stacking: two normal vectors of two rings are perpendicular and the distance between two centers is less than 5.5Å

π-cation interaction

• Positively-charged residues: Lys, Arg, His
• Positively-charged functional groups in the ligand: guanidine, ammonium, sulfonium
• π-cation interaction: angle between vector formed by cation and aromatic centers and aromatic plane is greater than 45° and the distance between cation and aromatic center is less than 5.5Å

Hydrophobic interaction

• PLIpp only takes into account of carbon atoms which are not directly linked with any other heteroatoms, such as: nitrogen, oxygen,...
• The distance between two carbon atoms is from 3.3 to 4.0Å

Electrostatic interaction

• Positively-charged residues: Lys, Arg, His
• Negatively-charged residues: Glu, Asp
• Positively-charged functional groups in the ligand: guanidine, ammonium, sulfonium
• Negatively-charged functional groups in the ligand: carboxylate, phosphate, sulfate
• The distance between positively-charged and negatively-charged species is less than 5.5Å

Hydrogen bond

• The angle of (Donor - Hydrogen - Acceptor) is greater than 130°
• The distance between HBA and HBD is from 2.5 to 3.8Å

Water bridge

• Similar geometric conditions as hydrogen bond
• PLIpp only considers three cases of water bridge:
  • Protein (donor 1) - Water (acceptor 1 and donor 2) - Ligand (acceptor 2)
  • Protein (donor 1) - Water (acceptor) - Ligand (donor 2)
  • Protein (acceptor 1) - Water (donor 1 and acceptor 2) - ligand (donor 2)

Halogen bond

• PLIpp only considers Cl, Br, I to make halogen bond
• The angle of (Halogen donor - Halogen - Halogen acceptor) is greater than 168°

Comparison with PLIP

PDB ID	Feature	PLIP	PLIpp
6XJK	Hydrophobic	Leu551, Ile559, Phe628, Leu680	Leu551, Ile559, Phe628, Leu680
	Cation-pi	Lys581	Lys581
	Pi-pi stack		Phe628 (Sandwich)
	Hydrogen bond	Lys581, Glu627, Val629	Lys581, Gln626, Glu627, Val 629, Asn678
	Water bridge	Gln626, Ser633	Ser633
3DY7	Hydrophobic	Leu118	Leu118, Phe209
	Pi-pi stack	Phe209 (T-shaped)	Phe209 (T-shaped)
	Hydrogen bond	Gly77, Asn78, Glu144, Met146, Ser150, Ser194	Asn78, Gly80, Lys97, Met143, Glu144, Met146, Ser150, Lys192, Ser212
	Electrostatic	Lys97, Lys192	Lys97, Lys192
	Halogen bond	Val127	Val127
4MHY	Hydrophobic	Phe317	Phe317
	Pi-pi stack	Phe317 (Sandwich), Trp321 (T-shaped)	Phe317 (Sandwich), Trp321 (T-shaped)
	Cation-pi		Trp189
	Hydrogen bond		Glu296, Trp321
	Electrostatic		Asp144, Glu183, Glu184, Asp238, Asp297
	Water bridge	Phe294, Phe317	Phe317
	Metal complex	Zn, Asp144, Glu184, His322
2OBJ	Hydrophobic	Ala65, Ile104, Leu120, Leu174, Ile185, Asp186	Val52, Ala65, Ile104, Leu120, Leu174, Ile185, Asp186
	Hydrogen bond	Lys67, Asp186	Lys67
	Water bridge	Asp186, Phe187
5N2F	Hydrophobic	Ile54, Tyr56, Met115, Ala121	Ile54, Tyr56, Met115, Ala121
	Hydrogen bond	Phe19, Gln66	Thr20, Gln66
	Pi-pi stack	Tyr56	Tyr56