Computational Investigation of Gantenerumab and Crenezumab's Recognition of Aβ Fibrils in Alzheimer's Disease Brain Tissue.

Chen, Yujie; Wei, Guanghong; Zhao, Jun; Nussinov, Ruth; Ma, Buyong

Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapies using antibodies to lower assembled Aβ 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-Aβ antibodies that bind multi-forms of Aβ, with different Aβ epitope preferences. Here, using molecular dynamic (MD) simulations, we study the binding of two antibodies to Aβ1-40 fibril, whose conformation is derived from AD patient's brain tissue. We find that gantenerumab recognizes Aβ1-11 monomer fragment only in slightly lower pH than physiological environment where His6 of Aβ1-11 is protonated. Both gantenerumab and crenezumab bind with integrated Aβ fibril rather than bind to monomers within the fibril. Gantenerumab preferentially binds to the N-terminal region of the Aβ1-40 fibril, which is driven by aromatic interactions. Crenezumab can recognize the N-terminal region, as well as the cross-section of the Aβ1-40 fibril, indicating its multiple binding modes in Aβ fibril recognition. These results demonstrate that conformation-dependent interactions of antibody-amyloid recognition.