Distinct structural features associated with conformational epitopes of amyloid β fibrils revealed using mathematical geometric measures

Monoclonal antibodies (mAbs) targeting the key pathogenic protein amyloid β (Aβ) peptide represent a promising therapeutic approach for treating Alzheimer’s disease (AD). Anti-Aβ mAbs are classified by their affinity to different states of Aβ, such as monomers, oligomers, protofibrils, and fibrils. Recently developed second-generation mAbs, which effectively remove Aβ plaques from the AD patients’ brains, exhibit specific avidity for Aβ oligomers, protofibrils, and fibrils. These mAbs target epitopes in specific conformations displayed on Aβ oligomers, protofibrils, or fibrils; thus, they are called conformational epitopes. However, the structural features of conformational epitopes are poorly understood. Here, we proposed geometric measures based on the mathematically defined writhe. We found that the conformational epitopes of Aβ in the 69 fibrils show distinctive geometric features compared to the other regions of Aβ, as evidenced by outlying values of the geometric measures. Mapping regions with higher measure values identifies potential conformational epitopes across various fibril forms. Results showed that some fibril forms exhibit geometrically distinct regions within the fibril structures, suggesting that these fibrils are less accessible to mAbs, impairing therapeutic effects targeting them. Our geometric measures reveal visually unidentified structural features of conformational epitopes in polymorphic Aβ fibrils, which relate to mAbs binding.