title: Integrating protein structures and precomputed genealogies in the Magnum database: examples with cellular retinoid binding proteins.
abstract: BACKGROUND
  When accurate models for the divergent evolution of protein sequences are integrated with complementary biological information, such as folded protein structures, analyses of the combined data often lead to new hypotheses about molecular physiology. This represents an excellent example of how bioinformatics can be used to guide experimental research. However, progress in this direction has been slowed by the lack of a publicly available resource suitable for general use.
  
  
  RESULTS
  The precomputed Magnum database offers a solution to this problem for ca. 1,800 full-length protein families with at least one crystal structure. The Magnum deliverables include 1) multiple sequence alignments, 2) mapping of alignment sites to crystal structure sites, 3) phylogenetic trees, 4) inferred ancestral sequences at internal tree nodes, and 5) amino acid replacements along tree branches. Comprehensive evaluations revealed that the automated procedures used to construct Magnum produced accurate models of how proteins divergently evolve, or genealogies, and correctly integrated these with the structural data. To demonstrate Magnum's capabilities, we asked for amino acid replacements requiring three nucleotide substitutions, located at internal protein structure sites, and occurring on short phylogenetic tree branches. In the cellular retinoid binding protein family a site that potentially modulates ligand binding affinity was discovered. Recruitment of cellular retinol binding protein to function as a lens crystallin in the diurnal gecko afforded another opportunity to showcase the predictive value of a browsable database containing branch replacement patterns integrated with protein structures.
  
  
  CONCLUSIONS
  We integrated two areas of protein science, evolution and structure, on a large scale and created a precomputed database, known as Magnum, which is the first freely available resource of its kind. Magnum provides evolutionary and structural bioinformatics resources that are useful for identifying experimentally testable hypotheses about the molecular basis of protein behaviors and functions, as illustrated with the examples from the cellular retinoid binding proteins.
authors.affiliation: Department of Chemistry, University of Florida, PO Box 117200, Gainesville, FL 32611, USA. mbradley@ffame.org
authors.forename: Michael E
authors.initials: ME
authors.lastname: Bradley
authors.forename: Steven A
authors.initials: SA
authors.lastname: Benner
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D003628:Database Management Systems; D030562:Databases, Protein; D019143:Evolution, Molecular; D016247:Information Storage and Retrieval / Q000379:methods; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010375:Pedigree; D011485:Protein Binding; D011487:Protein Conformation; D012177:Retinol-Binding Proteins / Q000737:chemistry* / Q000235:genetics*; D054840:Retinol-Binding Proteins, Cellular; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D012177:Retinol-Binding Proteins; D054840:Retinol-Binding Proteins, Cellular