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

Massih Khorvash,Andriy Kovalenko,Neil R Cashman,Jie Lu,Judith M Silverman,Nick Blinov,Ebrima Gibbs,Yu Tian Wang ,David S Wishart ,Carol L Ladner-Keay

doi:10.1371/journal.pone.0232266

Abstract

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

Highlights

The most common form of dementia is associated with Alzheimer’s disease (AD), which is a fatal neurodegenerative disorder [1]
The residues 25-29 of Aβ42 (GSNKG) with a solvent-exposed lysine in a sharp turn conformation were hypothesized to be the epitope of an Aβ oligomer (AβO) specific antibody [23]
It has been demonstrated that the m5E3 antibody has a much higher affinity for AβOs compared to amyloid β (Aβ) fibrils or monomers [23]

Summary

Introduction

The most common form of dementia is associated with Alzheimer’s disease (AD), which is a fatal neurodegenerative disorder [1]. Abundant presence of neurofibrillary tangles and senile amyloid plaques are displayed in individuals with AD [2]. The amyloid plaques predominantly composed of densely packed Aβ fibrils [3]. Aβ is the cleavage product of the transmembrane amyloid precursor protein by β- and γ-secretases. The chain length of Aβ varies depending on the cleavage site of γ-secretase [4]. The two most common forms of Aβ present

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