Open AccessMolecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates
Author(s) -
Massih Khorvash,
Nick Blinov,
Carol L. Ladner-Keay,
Jie Lu,
Judith M. Silverman,
Ebrima Gibbs,
Yu Tian Wang,
Andriy Kovalenko,
David S. Wishart,
Neil R. Cashman
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0232266
Subject(s) - oligomer , monoclonal antibody , epitope , antibody , chemistry , amyloid (mycology) , peptide , fibril , mutagenesis , biochemistry , microbiology and biotechnology , biophysics , biology , mutation , immunology , inorganic chemistry , organic chemistry , gene
Oligomeric amyloid β (A β ) is currently considered the most neurotoxic form of the A β peptide implicated in Alzheimer’s disease (AD). The molecular structures of the oligomers have remained mostly unknown due to their transient nature. As a result, the molecular mechanisms of interactions between conformation-specific antibodies and their A β oligomer (A β O) cognates are not well understood. A monoclonal conformation-specific antibody, m5E3, was raised against a structural epitope of A β oligomers. m5E3 binds to A β Os with high affinity, but not to A β monomers or fibrils. In this study, a computational model of the variable fragment (Fv) of the m5E3 antibody (Fv5E3) is introduced. We further employ docking and molecular dynamics simulations to determine the molecular details of the antibody-oligomer interactions, and to classify the A β Os as Fv5E3-positives and negatives, and to provide a rationale for the low affinity of Fv5E3 for fibrils. This information will help us to perform site-directed mutagenesis on the m5E3 antibody to improve its specificity and affinity toward oligomeric A β species. We also provide evidence for the possible capability of the m5E3 antibody to disaggregate A β Os and to fragment protofilaments.