Mechanisms of recognition of A{beta} monomer, oligomer, and fibril by homologous antibodies [Computational Biology]

Alzheimers' disease (AD) is one of the most devastating neurodegenerative diseases without effective therapies. Immunotherapy is a promising approach; but amyloidantibody structural information is limited. Here we simulate the recognition of monomeric, oligomeric, and fibril Aβ by three homologous antibodies (solanezumab, crenezumab, and their chimeric CreneFab). Solanezumab only binds the monomer, while crenezumab and CreneFab can recognize different oligomerization states; however, the structural basis for this observation is not understood. Here we successfully identified stable complexes of crenezumab with Aβ pentamer (oligomer model) and 16-mer (fibril model). Noteworthy, solanezumab targets Aβ residues 16-26 preferentially in the monomeric state; conversely, crenezumab consistently targets residues 13- 16 in different oligomeric states. Unlike the buried monomeric peptide in solanezumab's complementarity-determining region (CDR), crenezumab binds the oligomer's lateral and edge residues. Surprisingly, crenezumab's CDR loops can effectively bind the Aβ fibril lateral surface around the same 13-16 region. The constant domain influences antigen recognition through entropy redistribution. Different constant domain residues in solanezumab/crenezumab/chimera influence the binding of Aβ aggregates. Collectively, we provide molecular insight into the recognition mechanisms facilitating antibody design.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2xtkhq6
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