title: High-accuracy modeling of antibody structures by a search for minimum-energy recombination of backbone fragments.
abstract: Current methods for antibody structure prediction rely on sequence homology to known structures. Although this strategy often yields accurate predictions, models can be stereo-chemically strained. Here, we present a fully automated algorithm, called AbPredict, that disregards sequence homology, and instead uses a Monte Carlo search for low-energy conformations built from backbone segments and rigid-body orientations that appear in antibody molecular structures. We find cases where AbPredict selects accurate loop templates with sequence identity as low as 10%, whereas the template of highest sequence identity diverges substantially from the query's conformation. Accordingly, in several cases reported in the recent Antibody Modeling Assessment benchmark, AbPredict models were more accurate than those from any participant, and the models' stereo-chemical quality was consistently high. Furthermore, in two blind cases provided to us by crystallographers prior to structure determination, the method achieved <1.5 Ångstrom overall backbone accuracy. Accurate modeling of unstrained antibody structures will enable design and engineering of improved binders for biomedical research directly from sequence. Proteins 2016; 85:30-38. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Christoffer H
authors.identifier: 0000-0002-1450-4651
authors.initials: CH
authors.lastname: Norn
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Gideon
authors.initials: G
authors.lastname: Lapidoth
authors.affiliation: Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, 76100, Israel.
authors.forename: Sarel J
authors.initials: SJ
authors.lastname: Fleishman
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000906:Antibodies / Q000737:chemistry*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D015233:Models, Statistical; D009010:Monte Carlo Method; D011487:Protein Conformation; D012984:Software; D013816:Thermodynamics
chemical_list: D000906:Antibodies
keywords: AbDesign; combinatorial-backbone modeling; loop prediction; protein structure prediction; rosetta