Site-specific chirality-conferred structural compaction differentially mediates the cytotoxicity of A42

Growing evidence supports the confident association between distinct amyloid beta (A beta) isoforms and Alzheimer's Disease (AD) pathogenesis. As such, critical investigations seeking to uncover the translational factors contributing to A beta toxicity represent a venture of significant value. Herein, we comprehensively assess full-length A beta 42 stereochemistry, with a specific focus on models that consider naturally-occurring isomerization of Asp and Ser residues. We customize various forms of d-isomerized A beta as natural mimics, ranging from fragments containing a single d residue to full length A beta 42 that includes multiple isomerized residues, systematically evaluating their cytotoxicity against a neuronal cell line. Combining multidimensional ion mobility-mass spectrometry experimental data with replica exchange molecular dynamics simulations, we confirm that co-d-epimerization at Asp and Ser residues within A beta 42 in both N-terminal and core regions effectively reduces its cytotoxicity. We provide evidence that this rescuing effect is associated with the differential and domain-specific compaction and remodeling of A beta 42 secondary structure.