BioLiP: structure database for biologically relevant ligand-protein interactions

This is the source code for curating a local copy of the BioLiP database from mmCIF files of the PDB database and displaying the database content in web browser.

Installation for database update

cd script/
make

The compilation requires GCC with C++ 11 support. The binary executable of cd-hit, CSSR, and US-align are available at script/ for 64 bit Linux. When using other operating system, they can be recompiled:

# install script/cd-hit
cd cdhit/
make install
cd ..

# install script/CSSR
cd CSSR/
make install
cd ..

# install script/USalign script/pdb2xyz script/pdb2fasta script/xyz_sfetch
cd USalign
make install
cd ..

Additionally, we make the following binary executables available under script that should be reinstalled if not using 64 bit Linux:

• makeblastdb, blastn and blastp from the NCBI BLAST+
• foldseek from foldseek

Installation for web browsing

1. This repository contains a copy of JSmol under the jsmol folder. This is not needed for database update. It is solely for visualization through the web browser.

2. Optionally, to show directed acylic graph for Gene Ontology terms on the website, the dot program from Graphviz can be used. If your system does not have Graphviz, you can install it to graphviz/bin/dot from source code:

wget https://gitlab.com/api/v4/projects/4207231/packages/generic/graphviz-releases/6.0.2/graphviz-6.0.2.tar.gz
tar -xvf graphviz-6.0.2.tar.gz
mkdir ../graphviz
./configure --prefix=`readlink -e ../graphviz`
make
make install
rm graphviz-6.0.2.tar.gz

3. Follow output/readme.sh to set up for web browsing.

Database update

The first time to set up the database takes at least two days. Subsequent weekly updates only take a couple hours. The database would requires ~100GB of disk space, including ~60GB to store original mmCIF files downloaded from PDB (pdb/data/structures/divided/mmCIF/; see Step 11 to reduce this requirement), ~20GB to store intermediate PDB files (interim/), and another ~20GB to store final files (weekly/, data/ and download/).

Step 1: Download PDB entries

Run the following shell script the first time the database is created.

script/rsyncPDB.sh

This script downloads the initial set of mmCIF files for full asymetric unit to pdb/data/structures/divided/mmCIF. It will also download the resolution of pdb to pdb/derived_data/index/resolu.idx.

Alternatively, run the following script to download only the missing mmcif files and resolu.idx.

script/download_pdb.pl

Both script/rsyncPDB.sh and script/download_pdb.pl have the same purpose of downloading mmcif files and resolu.idx. For the first time the database is setup, script/rsyncPDB.sh must be used instead of script/download_pdb.pl because the later is much slower when a large number of files need be downloaded. For subsequent weekly update, either one of the script can be used. If you do not want to clean up the pdb/ folder, the first script script/rsyncPDB.sh is preferred. If you do want to clean up the pdb/ folder after every update, which can save ~60GB of disk space, you must use the second script script/download_pdb.pl to avoid re-downloading the whole pdb database every week. Hard disk space permitted, it is recommended to use script/rsyncPDB.sh, which offers faster download speed and less file corruption.

Step 2: Download SIFTS function annotation

This step can be performed in parallel to step 1.

./script/download_sifts.pl

This script downloads taxonomy, uniprot accession, EC, GO and pubmed ID to sifts/flatfiles/tsv and extract the data to data/*.tsv.gz. This script downloads gene ontology to obo/go/go-basic.obo. This script downloads swissprot to uniprot/current_release/knowledgebase/complete/uniprot_sprot.fasta.gz.

Optionally, run the following script to download csa. The manually curated dataset of csa is updated infrequently. Therefore, it is not necessary to run it every week.

./script/download_csa.pl

This script downloads catalytic site to m-csa/api/residues.json and extract the summary to data/csa.tsv.gz.

Step 3: Download binding affinity

This step must be performed after step 2 (regardless of step 1) because it requires the pdb to uniprot mapping file generated in the previous step.

./script/download_bind.pl

This script downloads BindingDB to bind/BindingDB* and extract the summary to data/BindingDB.tsv.gz. This script may have the warning: "gzip: bind/BindingDB_All_tsv.zip: invalid compressed data--length error", which is caused by decompressing zip with zcat. This warning can be ignored.

Optionally, run the following script to download MOAD. Since MOAD only updates every few years, it is not necessary to run it weekly.

./script/download_moad.pl

This script downloads MOAD to bind/every.csv and extract the summary to data/moad.tsv.

Again optionally, follow instructions at bind/README.md for how to semi-manually create PDBbind-CN summary at data/PDBbind.tsv. This only need to be peformed annually.

Step 4: download auxilary data

This step can be performed independent of step 1 to 8, but must be done before step 9.

./script/download_ligand.pl
./script/curate_smiles.pl

This script downloads CCD ligand to pdb/data/monomers/components.cif.gz and extract their summary to data/ligand.tsv.gz. This script downloads enzyme to enzyme/enzyme.dat and extract their summary to data/enzyme.tsv.gz.

Step 5: convert mmCIF to PDB format

This step must be performed after step 1 (regardless of step 2 to 4).

./script/curate_pdb.pl

This script converts mmCIF files from pdb/data/structures/divided/mmCIF to interim/*/*.tar.gz and interim/*/*.txt

Step 6: download pubmed abstract

This step must be performed after step 2 and 5 (regardless of step 3 and 4).

./script/download_pubmed.pl

This script checks interim/*/*.txt for artifact ligand and download pubmed abstract to pubmed/*.txt

Step 7: remove artifact and unbound ligand

This step must be performed after step 6.

./script/curate_ligand.pl

This script check potential artifact ligand listed by interim/*/*.txt against pubmed abstract at pubmed/*.txt. It repackages receptor and biologically relevent ligand pdb files into interim/*/*.tar.bz2. Binding sites are written to interim/*/*.bsr.

Step 8: prepare redundant dataset

This step must be performed after step 7.

./script/make_weekly.pl

This script reads interim/*/*.tar.bz2 and interim/*/*.bsr and writes weekly/receptor_*.tar.bz2, weekly/receptor1_*.tar.bz2, weekly/ligand_*.tar.bz2 and weekly/BioLiP_*.bsr.gz. FASTA sequence of protein, peptide, rna, dna are saved to data/*.fasta.gz

Step 9: prepare nonredundant dataset

This step must be performed after step 3, 4 and 8.

./script/make_nr.pl

This script converts weekly/BioLiP_*.bsr.gz to weekly/BioLiP_*.txt and weekly/BioLiP_*_nr.txt. It also creates weekly/receptor_*_nr.tar.bz2, weekly/receptor1_*_nr.tar.bz2 and weekly/ligand_*_nr.tar.bz2 from intermediate files of the previous step.

Step 10: assign RNA secondary structure

This step must be performed after step 8

./script/make_rSS.pl

This script assigns RNA secondary structure for weekly/ligand_*.tar.bz2 and store it at data/rna_ss.txt.gz.

Step 11: curate EC annotation

This step must be performed after step 8.

./script/make_EC.pl

This script reads EC from data/chain2ec.tsv.gz and extract the summary to data/ec_all.tsv.gz. It also creates weekly/Enzyme_*.tar.bz2.

Step 12: curate GO annotation

This step must be performed after step 11.

./script/curate_GO.pl

This script reads GO from obo/go/go-basic.obo, data/pdb_all.tsv.gz and data/ec_all.tsv.gz. It extracts the summary to data/go2name.tsv.gz, data/is_a.tsv.gz and data/pdb_go.tsv.gz. This script reads swissprot name from uniprot/current_release/knowledgebase/complete/uniprot_sprot.fasta.gz and extract the summary to data/uniprot_sprot.tsv.gz.

Step 13: make foldseek database

This step must be performed after step 9

./script/make_foldseek.pl

Thi script creates foldseek database at foldseek/

Step 14: curate rhea annotation

This step must be performed after step 12.

./script/download_rhea.pl

This script downloads firedb, rhea and chebi tofiredb/, rhea/, and chebi. It then maps protein receptors to rhea according to rhea/uniprot2rhea.tsv; if the uniprot protein is not in rhea, the protein is mapped to rhea according to its GO annotations at data/pdb_go.tsv.gz. The protein to rhea mappings are then written to data/pdb_rhea.tsv.gz. If a protein is present in this rhea mapping, the annotation score of the ligand interaction is calculated by the Tanimoto Coefficient between the ligand and the rhea ligands. Otherwise, the annotation score is categorized by firedb (cognate, ambiguous, non_coganate). The annotation score is saved to data/lig_rhea.tsv.gz.

Step 15: clean up intermediate files

This step must be run after everything is done.

./script/clean_up.pl

Reference

Chengxin Zhang, Xi Zhang, Peter L Freddolino and Yang Zhang (2023) BioLiP2: an updated structure database for biologically relevant ligand-protein interactions. Nucleic Acids Research, gkad630.