title: A threading-based method (FINDSITE) for ligand-binding site prediction and functional annotation.
abstract: 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 A 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 A. This is because analysis of weakly homologous protein models reveals that about half have a rmsd from the native binding site <2 A. 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.
authors.affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 250 14th Street NW, Atlanta, GA 30318, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Brylinski
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D001703:Biophysics / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D008024:Ligands; D008958:Models, Molecular; D015233:Models, Statistical; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry; D015203:Reproducibility of Results; D012984:Software
chemical_list: D008024:Ligands; D011506:Proteins