Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints
By J. A. Finn, Julia Koehler Leman, Jordan R. Willis, Alberto Cisneros, James E. Crowe Jr., Jens Meiler. 2016
24 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Radiology, Nuclear Medicine and Imaging
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In Molecular Biology
- Brian D. Weitzner
- Jeffrey J. Gray
- Jens Meiler
- Brian Joseph Bender
- Brennica Marlow
- David Baker
- Sergey Lyskov
- Michael Feig
In Radiology, Nuclear Medicine and Imaging
- Brian D. Weitzner
- Jeffrey J. Gray
- Brian Joseph Bender
- Brennica Marlow
- Jens Meiler
- Lim Heo
- Michael Feig
Citations in the corpus
- Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs (2020, methodology): “In particular this is analogous to research in antibody modeling in which protocols have been developed to model the long loops of the complementary determining regions [37,38].”
- Accurate structure prediction of CDR H3 loops enabled by a novel structure-based C-terminal constraint (2016, methodology): “Similarly, effort has been made to develop a CDR H3-specific loop modeling routine (21, 27, 28).”