title: Antibody structure determination using a combination of homology modeling, energy-based refinement, and loop prediction.
abstract: We present the blinded prediction results in the Second Antibody Modeling Assessment (AMA-II) using a fully automatic antibody structure prediction method implemented in the programs BioLuminate and Prime. We have developed a novel knowledge based approach to model the CDR loops, using a combination of sequence similarity, geometry matching, and the clustering of database structures. The homology models are further optimized with a physics-based energy function (VSGB2.0), which improves the model quality significantly. H3 loop modeling remains the most challenging task. Our ab initio loop prediction performs well for the H3 loop in the crystal structure context, and allows improved results when refining the H3 loops in the context of homology models. For the 10 human and mouse derived antibodies in this assessment, the average RMSDs for the homology model Fv and framework regions are 1.19 Å and 0.74 Å, respectively. The average RMSDs for five non-H3 CDR loops range from 0.61 Å to 1.05 Å, and the H3 loop average RMSD is 2.91 Å using our knowledge-based loop prediction approach. The ab initio H3 loop predictions yield an average RMSD of 1.28 Å when performed in the context of the crystal structure and 2.67 Å in the context of the homology modeled structure. Notably, our method for predicting the H3 loop in the crystal structure environment ranked first among the seven participating groups in AMA-II, and our method made the best prediction among all participants for seven of the ten targets.
authors.affiliation: Schrodinger, LLC, New York, New York, 10036.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.forename: Tyler
authors.initials: T
authors.lastname: Day
authors.forename: Dora
authors.initials: D
authors.lastname: Warshaviak
authors.forename: Colleen
authors.initials: C
authors.lastname: Murrett
authors.forename: Richard
authors.initials: R
authors.lastname: Friesner
authors.forename: David
authors.initials: D
authors.lastname: Pearlman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D022801:Complementarity Determining Regions / Q000737:chemistry; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry*; D007135:Immunoglobulin Variable Region / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D000906:Antibodies; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region
keywords: CDRs; H3 loop; HCDR3; antibody engineering; antibody modeling assessment; antibody structure modeling; energy function; loop prediction; protein structure prediction