GalaxySite: ligand-binding-site prediction by using molecular docking

Abstract

Knowledge of ligand-binding sites of proteins provides invaluable information for functional studies, drug design and protein design. Recent progress in ligand-binding-site prediction methods has demonstrated that using information from similar proteins of known structures can improve predictions. The GalaxySite web server, freely accessible at http://galaxy.seoklab.org/site, combines such information with molecular docking for more precise binding-site prediction for non-metal ligands. According to the recent critical assessments of structure prediction methods held in 2010 and 2012, this server was found to be superior or comparable to other state-of-the-art programs in the category of ligand-binding-site prediction. A strong merit of the GalaxySite program is that it provides additional predictions on binding ligands and their binding poses in terms of the optimized 3D coordinates of the protein-ligand complexes, whereas other methods predict only identities of binding-site residues or copy binding geometry from similar proteins. The additional information on the specific binding geometry would be very useful for applications in functional studies and computer-aided drug discovery.

Figure 1.

Flowchart of the GalaxySite algorithm. The ligand-binding site of a protein is predicted by protein–ligand docking. The protein structure required for the docking simulation may be provided by the user or predicted from the protein sequence. The binding ligand is predicted from similar protein–ligand complexes in the structure database. The molecular docking algorithm LigDockCSA is used with a hybrid energy of AutoDock3 energy and restraint energy derived from similar protein–ligand complexes. Binding-site residues are extracted from the docking pose.

Figure 2.

Performance comparison of GalaxySite with other server methods in terms of median Matthews correlation coefficient (MCC) on the CASP9 (top), CASP10 (middle) and CAMEO (bottom) ligand-binding-site prediction category targets. In the figure, the SEOK-SERVER method used GalaxySite in the CASP blind prediction.

Figure 3.

GalaxySite output page. Predicted ligands, their two-dimensional structures and templates for protein–ligand complexes are tabulated. Ligand names and PDB IDs are linked to the RCSB PDB website for detailed information. Predicted ligand-binding residues for each ligand are also listed. Predicted binding poses are shown in static images, which can be viewed using the Jmol structure viewer or can be downloaded in PDB format.