title: Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints.
abstract: Structural restrictions are present even in the most sequence diverse portions of antibodies, the complementary determining region (CDR) loops. Previous studies identified robust rules that define canonical structures for five of the six CDR loops, however the heavy chain CDR 3 (HCDR3) defies standard classification attempts. The HCDR3 loop can be subdivided into two domains referred to as the "torso" and the "head" domains and two major families of canonical torso structures have been identified; the more prevalent "bulged" and less frequent "non-bulged" torsos. In the present study, we found that Rosetta loop modeling of 28 benchmark bulged HCDR3 loops is improved with knowledge-based structural restraints developed from available antibody crystal structures in the PDB. These restraints restrict the sampling space Rosetta searches in the torso domain, limiting the φ and ψ angles of these residues to conformations that have been experimentally observed. The application of these restraints in Rosetta result in more native-like structure sampling and improved score-based differentiation of native-like HCDR3 models, significantly improving our ability to model antibody HCDR3 loops.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Finn
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Koehler Leman
authors.affiliation: Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Jordan R
authors.identifier: 0000-0002-0135-5263
authors.initials: JR
authors.lastname: Willis
authors.affiliation: Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Cisneros
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, United States of America.|Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee, United States of America.|Vanderbilt Vaccine Center, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: James E
authors.initials: JE
authors.lastname: Crowe
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee, United States of America.|Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, United States of America.|Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee, United States of America.
authors.forename: Jens
authors.initials: J
authors.lastname: Meiler
mesh_terms: D000465:Algorithms; D016000:Cluster Analysis; D022801:Complementarity Determining Regions / Q000737:chemistry*; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region