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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4868311?pdf=render |
| _version_ | 1828493652882620416 |
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| author | Jessica A Finn Julia Koehler Leman Jordan R Willis Alberto Cisneros James E Crowe Jens Meiler |
| author_facet | Jessica A Finn Julia Koehler Leman Jordan R Willis Alberto Cisneros James E Crowe Jens Meiler |
| author_sort | Jessica A Finn |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T11:42:32Z |
| format | Article |
| id | doaj.art-95d9151e4e9d4a5c86ca3df27dbc6d1c |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T11:42:32Z |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-95d9151e4e9d4a5c86ca3df27dbc6d1c2022-12-22T01:08:35ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01115e015481110.1371/journal.pone.0154811Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints.Jessica A FinnJulia Koehler LemanJordan R WillisAlberto CisnerosJames E CroweJens MeilerStructural 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.http://europepmc.org/articles/PMC4868311?pdf=render |
| spellingShingle | Jessica A Finn Julia Koehler Leman Jordan R Willis Alberto Cisneros James E Crowe Jens Meiler Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints. PLoS ONE |
| title | Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints. |
| title_full | Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints. |
| title_fullStr | Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints. |
| title_full_unstemmed | Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints. |
| title_short | Improving Loop Modeling of the Antibody Complementarity-Determining Region 3 Using Knowledge-Based Restraints. |
| title_sort | improving loop modeling of the antibody complementarity determining region 3 using knowledge based restraints |
| url | http://europepmc.org/articles/PMC4868311?pdf=render |
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