Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints

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 standa...

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Bibliographic Details
Published in:PloS one 2016-05, Vol.11 (5), p.e0154811-e0154811
Main Authors: Finn, Jessica A, Koehler Leman, Julia, Willis, Jordan R, Cisneros, 3rd, Alberto, Crowe, Jr, James E, Meiler, Jens
Format: Article
Language:English
Subjects:
Algorithms
Analysis
Antibodies
Antigens
Bioinformatics
Biology
Biology and Life Sciences
Cluster Analysis
Complementarity
Complementarity Determining Regions - chemistry
Complementarity-determining region
Complementarity-determining region 3
Constraints
Crystal structure
Genes
Health aspects
Immunoglobulin Heavy Chains - chemistry
Immunoglobulin Variable Region - chemistry
Immunoglobulins
Immunology
Knowledge bases (artificial intelligence)
Medicine and Health Sciences
Modelling
Models, Molecular
Physical Sciences
Protein Conformation
Proteins
Research and Analysis Methods
Robotics
Sampling
Structure-Activity Relationship
T cell receptors
Torso
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0154811