title: FINDSITE-metal: integrating evolutionary information and machine learning for structure-based metal-binding site prediction at the proteome level.
abstract: The rapid accumulation of gene sequences, many of which are hypothetical proteins with unknown function, has stimulated the development of accurate computational tools for protein function prediction with evolution/structure-based approaches showing considerable promise. In this article, we present FINDSITE-metal, a new threading-based method designed specifically to detect metal-binding sites in modeled protein structures. Comprehensive benchmarks using different quality protein structures show that weakly homologous protein models provide sufficient structural information for quite accurate annotation by FINDSITE-metal. Combining structure/evolutionary information with machine learning results in highly accurate metal-binding annotations; for protein models constructed by TASSER, whose average Cα RMSD from the native structure is 8.9 Å, 59.5% (71.9%) of the best of top five predicted metal locations are within 4 Å (8 Å) from a bound metal in the crystal structure. For most of the targets, multiple metal-binding sites are detected with the best predicted binding site at rank 1 and within the top two ranks in 65.6% and 83.1% of the cases, respectively. Furthermore, for iron, copper, zinc, calcium, and magnesium ions, the binding metal can be predicted with high, typically 70% to 90%, accuracy. FINDSITE-metal also provides a set of confidence indexes that help assess the reliability of predictions. Finally, we describe the proteome-wide application of FINDSITE-metal that quantifies the metal-binding complement of the human proteome. FINDSITE-metal is freely available to the academic community at http://cssb.biology.gatech.edu/findsite-metal/.
authors.affiliation: Center for the Study of Systems Biology, Georgia Institute of Technology, Atlanta, Georgia 30318, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Brylinski
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
mesh_terms: D000465:Algorithms; D001185:Artificial Intelligence; D001665:Binding Sites; D005075:Biological Evolution; D008670:Metals / Q000737:chemistry*; D011487:Protein Conformation; D020543:Proteome
chemical_list: D008670:Metals; D020543:Proteome