RESUMEN
Oligomeric amyloid ß (Aß) is currently considered the most neurotoxic form of the Aß 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 Aß oligomer (AßO) cognates are not well understood. A monoclonal conformation-specific antibody, m5E3, was raised against a structural epitope of Aß oligomers. m5E3 binds to AßOs with high affinity, but not to Aß 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 AßOs 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 Aß species. We also provide evidence for the possible capability of the m5E3 antibody to disaggregate AßOs and to fragment protofilaments.