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Computational Investigation of Gantenerumab and Crenezumab Recognition of A beta Fibrils in Alzheimer's Disease Brain Tissue

  1. Author:
    Chen, Yujie
    Wei, Guanghong
    Zhao, Jun
    Nussinov,Ruth
    Ma, Buyong

  2. Author Address

    Fudan Univ, State Key Lab Surface Phys, Dept Phys, Shanghai 200438, Peoples R China.Fudan Univ, Key Lab Computat Phys Sci MOE, Multiscale Res Inst Complex Syst, Shanghai 200438, Peoples R China.Leidos Biomed Res Inc, Basic Sci Program, Computat Struct Biol Sect, Frederick Natl Lab Canc Res,Natl Canc Inst Freder, Frederick, MD 21702 USA.Tel Aviv Univ, Sackler Inst Mol Med, Dept Human Genet & Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel.Shanghai Jiao Tong Univ, Engn Res Ctr Cell & Therapeut Antibody MOE, Sch Pharm, Shanghai 200240, Peoples R China.
    1. Year: 2020
    2. Date: OCT 21
  2. Journal: ACS CHEMICAL NEUROSCIENCE
  3. AMER CHEMICAL SOC,
    1. 11
    2. 20
    3. Pages: 3233-3244
  5. Type of Article: Article
  6. ISSN: 1948-7193
  1. Abstract:

    Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapies using antibodies to lower assembled provide a promising approach and have been widely studied. Anti-amyloid antibodies are often selective to amyloid conformation, and the lack of amyloid-antibody structural information limits our understanding of these antibodies' conformation selection. Gantenerumab and crenezumab are two anti-A beta antibodies that bind multiple forms of A beta with different epitope preferences. Here, using molecular dynamic (MD) simulations, we study the binding of these two antibodies to the A beta(1-)(40) fibril, whose conformation is derived from an AD patient's brain tissue. We find that gantenerumab recognizes the A beta(1-11) monomer fragment only at slightly lower pH than the physiological environment where His6 of A beta(1-)(11) is protonated. Both gantenerumab and crenezumab bind with integrated A beta fibril rather than binding to monomers within the fibril. Gantenerumab preferentially binds to the N-terminal region of the A beta(1-)(40) fibril, and the binding is driven by aromatic interactions. Crenezumab can recognize the N-terminal region, as well as the cross-section of the A beta(1-40) fibril, indicating its multiple binding modes in A beta fibril recognition. These results demonstrate conformation-dependent interactions of antibody-amyloid recognition.

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External Sources

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  2. DOI: 10.1021/acschemneuro.0c00364
  3. View record in Web of Science®
  4. WOS: 000584491300010

Library Notes

  1. Fiscal Year: FY2020-2021
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