title: Antibody modeling assessment.
abstract: A blinded study to assess the state of the art in three-dimensional structure modeling of the variable region (Fv) of antibodies was conducted. Nine unpublished high-resolution x-ray Fab crystal structures covering a wide range of antigen-binding site conformations were used as benchmark to compare Fv models generated by four structure prediction methodologies. The methodologies included two homology modeling strategies independently developed by CCG (Chemical Computer Group) and Accerlys Inc, and two fully automated antibody modeling servers: PIGS (Prediction of ImmunoGlobulin Structure), based on the canonical structure model, and Rosetta Antibody Modeling, based on homology modeling and Rosetta structure prediction methodology. The benchmark structure sequences were submitted to Accelrys and CCG and a set of models for each of the nine antibody structures were generated. PIGS and Rosetta models were obtained using the default parameters of the servers. In most cases, we found good agreement between the models and x-ray structures. The average rmsd (root mean square deviation) values calculated over the backbone atoms between the models and structures were fairly consistent, around 1.2 Å. Average rmsd values of the framework and hypervariable loops with canonical structures (L1, L2, L3, H1, and H2) were close to 1.0 Å. H3 prediction yielded rmsd values around 3.0 Å for most of the models. Quality assessment of the models and the relative strengths and weaknesses of the methods are discussed. We hope this initiative will serve as a model of scientific partnership and look forward to future antibody modeling assessments.
authors.affiliation: Centocor R&D, Inc, Radnor, Pennsylvania 19087, USA. jcalmagro@hotmail.com
authors.forename: Juan C
authors.initials: JC
authors.lastname: Almagro
authors.forename: Mary Pat
authors.initials: MP
authors.lastname: Beavers
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernandez-Guzman
authors.forename: Johannes
authors.initials: J
authors.lastname: Maier
authors.forename: Jodi
authors.initials: J
authors.lastname: Shaulsky
authors.forename: Kenneth
authors.initials: K
authors.lastname: Butenhof
authors.forename: Paul
authors.initials: P
authors.lastname: Labute
authors.forename: Nels
authors.initials: N
authors.lastname: Thorsteinson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kelly
authors.forename: Alexey
authors.initials: A
authors.lastname: Teplyakov
authors.forename: Jinquan
authors.initials: J
authors.lastname: Luo
authors.forename: Raymond
authors.initials: R
authors.lastname: Sweet
authors.forename: Gary L
authors.initials: GL
authors.lastname: Gilliland
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D001666:Binding Sites, Antibody; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000737:chemistry*; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D051381:Rats; D016415:Sequence Alignment; D012984:Software
chemical_list: D000906:Antibodies; D007135:Immunoglobulin Variable Region