Lin_F9 tutorial

Lin_F9 is a linear empirical scoring function for protein-ligand docking.

Preparation

Download a fork of Smina docking suite with Lin_F9 as an optional built-in scoring function at https://github.com/cyangNYU/Lin_F9_test

Take one protein-ligand complex (PDB_id: 1eby) as an example:

Initial files of 1eby_ligand.mol2 and 1eby_protein.pdb obtained from PDBbind database

MGLTools are used for preparing PDBQT files: 1eby_ligand.pdbqt and 1eby_protein.pdbqt.

(MGLTools can be downloaded at http://mgltools.scripps.edu/downloads)

Local optimization

./smina.static -r 1eby_protein.pdbqt -l 1eby_ligand.pdbqt --local_only --scoring Lin_F9 -o 1eby_optimized.pdb 

Print the score of locally optimized pose.

grep 'Affinity' 1eby_optimized.pdb | awk '{print $3}'

Flexible re-docking

./smina.static -r 1eby_protein.pdbqt -l 1eby_ligand.pdbqt --autobox_ligand 1eby_ligand.pdbqt --scoring Lin_F9 -o 1eby_flexRedock.pdb

Print the score of the best-scored pose

grep -m1 'Affinity' 1eby_flexRedock.pdb | awk '{print $3}'

Calculate the RMSD between the best-scored pose and crystal ligand pose

(DockRMSD is used to calculate RMSD, can be downloaded at https://zhanglab.ccmb.med.umich.edu/DockRMSD/)

python split_docked.py 1eby_flexRedock.pdb 1eby_flexRedock
./calc_rmsd_for_pose.sh 1eby_flexRedock/1eby_flexRedock_01.pdb 1eby_ligand.mol2

End-to-end (E2E) docking

1. OpenBabel 2.4.1 used to generate maximum 10 conformers per ligand.

babel -imol2 1eby_ligand.mol2 -osdf 1eby_ligand_2D.sdf --gen2D 

babel -isdf 1eby_ligand_2D.sdf -osdf 1eby_ligand_3D.sdf --gen3D 

obabel 1eby_ligand_3D.sdf -O conformers.sdf --conformer --nconf 10 --score rmsd --writeconformers

2. All conformers are sequentially docked to protein receptor structure using flexible docking.

python split_sdf.py conformers.sdf 1eby_conformers/
./E2E_docking.sh

Print the score of the best-scored pose

grep -m1 'Affinity' 1eby_E2E/*.pdb | sort -nk3 | head -n 1 | awk '{print $3}'

Calculate the RMSD between the best-scored pose and crystal ligand pose

./GetSplit.sh
./calc_rmsd_for_pose.sh 1eby_E2E_top1.pdb 1eby_ligand.mol2

Reference

Chao Yang and Yingkai Zhang, J. Chem. Inf. Model., 61, 4630 - 4644, (2021).

Lin_F9: A Linear Empirical Scoring Function for Protein–Ligand Docking.