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Antibodies (Basel). 2018 Jul 13;7(3). pii: E25. doi: 10.3390/antib7030025.

Molecular Recognition between Aβ-Specific Single-Domain Antibody and Aβ Misfolded Aggregates.

Author information

1
Department of Chemical & Biomolecular Engineering, the University of Akron, Akron, OH 44325, USA. mingzhen.zhang@nih.gov.
2
Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. mingzhen.zhang@nih.gov.
3
Department of Chemical & Biomolecular Engineering, the University of Akron, Akron, OH 44325, USA. zhengj@uakron.edu.
4
Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. nussinor@mail.nih.gov.
5
Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. nussinor@mail.nih.gov.
6
Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. mabuyong@mail.nih.gov.

Abstract

Aβ is the toxic amyloid polypeptide responsible for Alzheimer's disease (AD). Prevention and elimination of the Aβ misfolded aggregates are the promising therapeutic strategies for the AD treatments. Gammabody, the Aβ-Specific Single-domain (VH) antibody, recognizes Aβ aggregates with high affinity and specificity and reduces their toxicities. Employing the molecular dynamics simulations, we studied diverse gammabody-Aβ recognition complexes to get insights into their structural and dynamic properties and gammabody-Aβ recognitions. Among many heterogeneous binding modes, we focused on two gammabody-Aβ recognition scenarios: recognition through Aβ β-sheet backbone and on sidechain surface. We found that the gammabody primarily uses the complementarity-determining region 3 (CDR3) loop with the grafted Aβ sequence to interact with the Aβ fibril, while CDR1/CDR2 loops have very little contact. The gammabody-Aβ complexes with backbone binding mode are more stable, explaining the gammabody's specificity towards the C-terminal Aβ sequence.

KEYWORDS:

Alzheimer’s disease; Aβ peptide; amyloid antibody; antibody recognition; single-domain antibodies

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