Docking tools and scaffold libs for Targeting SARS-CoV-2 Receptor Binding Domain and Main Protease with D-peptides

This repository is the source code and tutorial for Targeting SARS-CoV-2 Receptor Binding Domain and Main Protease with D-peptides, including curved helical scaffold library generation and D-peptide docking program. If you have any questions, feel free to discuss in Issues.

Installation

Note: Ubuntu 20.04 is recommended.

git clone https://github.com/laiyii/D-peptide-binder-design.git .
vim ~/.bashrc
export DPEP="/path/to/D-peptide-binder-design/source_code"
source ~/.bashrc

Tutorial

Curved helical scaffold library generation

You can generate scaffolds with customized needs.

gcc $DPEP/curved_lib/script/PhiPsi2Helix.c -o $DPEP/curved_lib/script/PhiPsi2Helix -lm

Running PhiPsi2Helix to generate scaffolds with given parameters:

chmod +x $DPEP/curved_lib/script/curl_helix_gen.sh
$DPEP/curved_lib/script/curl_helix_gen.sh -outdir <output_directory> -len <length> -paramlist <csv_file>

where -outdir defines the output directory, -len is the length of the polyALA sequence. Range of other parameters are defined in <csv_file> (see $DPEP/curled_lib/script/input_params.csv), and output pdb file is named as H_<len>_<phi0>_<delphi>_<psi0>_<delpsi>_<phase>.pdb. We also provide helix scaffold library at various lengths (28 aa and 35 aa) already generated in this work. Click here (extraction code: 14kv) to download.

Tutorial for helix scaffold fitting

Flip the target segment into D-type

Before docking, please flip your target segment to D-type, with residue names unchanged. Note that input file type should be a pdb file with hydrogens removed.

chmod +x $DPEP/docking/mirror_target/mirror_target.sh
$DPEP/docking/mirror_target/mirror_target.sh -i your_input_file.pdb -o your_output_file.pdb

The default output of -o is your_input_file_mirror.pdb

L- scaffold fitting to D- reference segment

You can fit scaffolds to extracted D- reference helical segment.

gcc $DPEP/docking/ScaffoldFitting/FitequationD.c -o $DPEP/docking/ScaffoldFitting/FitequationD -lm

Running FitequationD to generate fitted scaffolds:

$DPEP/docking/ScaffoldFitting/FitequationD [Dhelixtemplate.pdb] [fitted_output.pdb] [startResidueForFit default:0]

where Dhelixtemplate.pdb refers to the flipped target segment, fitted_output.pdb is the file name for fitted results. 'startResidueForFit' defines the start residue for fitting.

Tutorial for HelixScaffoldDocking

Flip the target into D-type

Before docking, please flip your target to D-type as mentioned above.

Surface residues remark

To generate grid scores, we need to define surface atoms (with atom-wise SASA larger than 1 Ų).

./naccess your_input_file_mirror.pdb

Note: For usage of naccess, see Naccess homepage.

With the asa file, we will edit the target structure file at column 70. Surface atoms are marked as 1, while internal atoms are 0:

python3 $DPEP/docking/mirror_target/surf_protein.py -i_asa mono_mirror_noh.asa -i your_input_file_mirror.pdb -o your_input_file_mirror_surf.pdb

-i_asa is the output file of Naccess.

Docking process

Compile the file first.

gcc $DPEP/docking/HelixScaffoldDocking/HelixScaffoldDocking_batch.c -o $DPEP/docking/HelixScaffoldDocking/HelixScaffoldDocking_batch -lm

Running the program with:

chmod +x ./$DPEP/docking/HelixScaffoldDocking/HSD_batch.sh
./$DPEP/docking/HelixScaffoldDocking/HSD_batch.sh -t target_processed.pdb -b batch_info -a central_atom_id

Docking tasks are performed in batch. The input options include:

• -t Processed target structure.
• -b A text file containing input scaffolds location and output file names.
• -a Atom ID, the ID of atom as the center of docking box.

Here's an example for batch_info:

$DPEP/docking/HelixScaffoldDocking/batch_info_example

The input scaffold file and output file are separated by spaces.

About database

We provide information of helix ligand-protein complex database in $DPEP/database/Hlig_protein_database.csv, which contains PDBID, residue numbers of helical ligands and fitting results.

License

This project is licensed under the MIT License - see the LICENSE file for details.

Acknowledgements

This design procedure involves multiple softwares related to protein design. We acknowledge and thank the developers of Naccess, Rosetta, gromacs, gmx_MMPBSA, AggreScan and PASTA2.0 for their incredible and hard work.