BioLiP: a semi-manually curated database for biologically relevant ligand-protein interactions

Abstract

BioLiP (http://zhanglab.ccmb.med.umich.edu/BioLiP/) is a semi-manually curated database for biologically relevant ligand-protein interactions. Establishing interactions between protein and biologically relevant ligands is an important step toward understanding the protein functions. Most ligand-binding sites prediction methods use the protein structures from the Protein Data Bank (PDB) as templates. However, not all ligands present in the PDB are biologically relevant, as small molecules are often used as additives for solving the protein structures. To facilitate template-based ligand-protein docking, virtual ligand screening and protein function annotations, we develop a hierarchical procedure for assessing the biological relevance of ligands present in the PDB structures, which involves a four-step biological feature filtering followed by careful manual verifications. This procedure is used for BioLiP construction. Each entry in BioLiP contains annotations on: ligand-binding residues, ligand-binding affinity, catalytic sites, Enzyme Commission numbers, Gene Ontology terms and cross-links to the other databases. In addition, to facilitate the use of BioLiP for function annotation of uncharacterized proteins, a new consensus-based algorithm COACH is developed to predict ligand-binding sites from protein sequence or using 3D structure. The BioLiP database is updated weekly and the current release contains 204 223 entries.

Figure 1.

Flowchart for the biological relevance assessment of ligand molecules.

Figure 2.

Distribution of ligands in BioLiP. ‘Regular’ represents the common small-molecule ligands except for the DNA/RNA, peptide, k-mer and metal ligands.

Figure 3.

An example of the function annotation in BioLiP. The annotation is for the chain A of the protein ‘purine nucleoside phosphorylase’ (PDB ID: 1A69). As can be seen from the Ligand-Binding/Catalytic Sites section, the ligand ‘Formycin B’ (ligand ID: FMB) binds to this protein with binding affinity K_i = 5 μM. The ligand–protein interaction is visualized by the Jmol Applet globally and locally and the 3D structures of the ligand and the protein can be downloaded. The ligand-binding/catalytic site residues are listed in this section as well. The EC number and GO terms together with their names are presented in the Enzyme Commission and Gene Ontology sections. Cross-references to other databases (PDB, UniProt, PDBsum, PDBe and PubMed) are appended in the External Links section.

Figure 4.

The COACH ligand-binding sites prediction results. The confidence score (Cscore) and the predicted binding site residues by COACH are presented in the first table, which is also visualized by Jmol Applet on the left panel. The top five predictions of other five individual methods are briefly summarized in the second table.