Journal
PROTEIN ENGINEERING DESIGN & SELECTION
Volume 29, Issue 11, Pages 477-484Publisher
OXFORD UNIV PRESS
DOI: 10.1093/protein/gzw028
Keywords
antibody; CDR-H3 loop; multicanonical molecular dynamics simulation; free energy landscape; crystal packing
Funding
- Japan Society for the Promotion of Science (JSPS) [16K07331]
- JSPS [24118008, 16K14711]
- Cooperative Research Program of the Institute for Protein Research, Osaka University [CR-15-05]
- HPCI [hp150146]
- Grants-in-Aid for Scientific Research [16K14711, 24118001, 16K07331, 24118008] Funding Source: KAKEN
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The antigen-binding site of antibodies, also known as complementarity-determining region (CDR), has hypervariable sequence properties. In particular, the third CDR loop of the heavy chain, CDR-H3, has such variability in its sequence, length, and conformation that ordinary modeling techniques cannot build a high-quality structure. At Stage 2 of the Second Antibody Modeling Assessment (AMA-II) held in 2013, the model structures of the CDR-H3 loops were submitted by the seven modelers and were critically assessed. After our participation in AMA-II, we rebuilt one of the long CDR-H3 loops with 13 residues (A52 antibody) by a more precise method, using enhanced conformational sampling with the explicit water model, as compared to our previous method employed at AMA-II. The current stable models obtained from the free energy landscape at 300 K include structures similar to the X-ray crystal structures. Those models were not built in our previous work at AMA-II. The current free energy landscape suggested that the CDR-H3 loop structures in the crystal are not stable in solution, but they are stabilized by the crystal packing effect.
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