Molecular interactions between monoclonal oligomer-specific antibody 5E3 and its amyloid beta cognates

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.