From monomer to fibril: Abeta‐amyloid binding to Aducanumab antibody studied by molecular dynamics simulation

Abstract

Abstract Alzheimer's disease is one of the most common causes of dementia. It is believed that the aggregation of short A β ‐peptides to form oligomeric and protofibrillar amyloid assemblies plays a central role for disease‐relevant neurotoxicity. In recent years, passive immunotherapy has been introduced as a potential treatment strategy with anti‐amyloid antibodies binding to A β ‐amyloids and inducing their subsequent degradation by the immune system. Although so far mostly unsuccessful in clinical studies, the high‐dosed application of the monoclonal antibody Aducanumab has shown therapeutic potential that might be attributed to its much greater affinity to A β ‐aggregates vs monomeric A β ‐peptides. In order to better understand how Aducanumab interacts with aggregated A β ‐forms compared to monomers, we have generated structural model complexes based on the known structure of Aducanumab in complex with an A β 2 − 7 ‐eptitope. Structural models of Aducanumab bound to full‐sequence A β 1 − 40 ‐monomers, oligomers, protofilaments and mature fibrils were generated and investigated using extensive molecular dynamics simulations to characterize the flexibility and possible additional interactions. Indeed, an aggregate‐specific N‐terminal binding motif was found in case of Aducanumab binding to oligomers, protofilaments and fibrils that is located next to but not overlapping with the epitope binding site found in the crystal structure with A β 2 − 7 . Analysis of binding energetics indicates that this motif binds weaker than the epitope but likely contributes to Aducanumab's preference for aggregated A β ‐species. The predicted aggregate‐specific binding motif could potentially serve as a basis to reengineer Aducanumab for further enhanced preference to bind A β ‐aggregates vs monomers.

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