threading-based method (FINDSITE) for ligand-binding site prediction and functional annotation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 1; pp. 129 - 134
• Main Authors: Brylinski, Michal, Skolnick, Jeffrey
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 08.01.2008; National Acad Sciences
• Subjects: Accuracy; Algorithms; Binding Sites; Biological Sciences; Biophysics - methods; Center of mass; Chemical properties; Computational Biology - methods; Crystal structure; Crystallography, X-Ray - methods; Datasets; Libraries; Ligands; Modeling; Models, Molecular; Models, Statistical; Molecular Conformation; Molecules; Nucleic acids; Predictions; Protein Binding; Protein Conformation; Protein Interaction Mapping; Proteins; Proteins - chemistry; Reproducibility of Results; Software
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0707684105

The detection of ligand-binding sites is often the starting point for protein function identification and drug discovery. Because of inaccuracies in predicted protein structures, extant binding pocket-detection methods are limited to experimentally solved structures. Here, FINDSITE, a method for ligand-binding site prediction and functional annotation based on binding-site similarity across groups of weakly homologous template structures identified from threading, is described. For crystal structures, considering a cutoff distance of 4 Å as the hit criterion, the success rate is 70.9% for identifying the best of top five predicted ligand-binding sites with a ranking accuracy of 76.0%. Both high prediction accuracy and ability to correctly rank identified binding sites are sustained when approximate protein models (<35% sequence identity to the closest template structure) are used, showing a 67.3% success rate with 75.5% ranking accuracy. In practice, FINDSITE tolerates structural inaccuracies in protein models up to a rmsd from the crystal structure of 8-10 Å. This is because analysis of weakly homologous protein models reveals that about half have a rmsd from the native binding site <2 Å. Furthermore, the chemical properties of template-bound ligands can be used to select ligand templates associated with the binding site. In most cases, FINDSITE can accurately assign a molecular function to the protein model.