Emergence of Alternative Structures in Amyloid Beta 1-42 Monomeric Landscape by N-terminal Hexapeptide Amyloid Inhibitors

Abstract

Alzheimer’s disease (AD) is characterized by deposition of amyloid beta (Aβ) peptides into senile plaques in the brain. While most familial mutations are associated with early-onset AD, recent studies report the AD-protective nature of two genetic human Aβ variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V Aβ1-6 (Aβ₆) hexapeptide and WT Aβ1–42 (Αβ₄₂) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T Aβ₆ hexapeptide binding on the monomeric WT Aβ₄₂ landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of Aβ₄₂ with the A2V and A2T hexapeptides compared to WT Aβ₆. A notable reorganization of the Aβ₄₂ landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, Aβ₆-bound Aβ₄₂ monomer exhibits alternative structural features that are strongly dependent on the hexapeptide sequence. For example, a central helix is more frequently populated within the A2T-bound monomer, while A2V-bound Aβ₄₂ is often enhanced in overall disorder. Taken together, the present simulations offer novel molecular insights onto the effect of the N-terminal hexapeptide binding on the Aβ₄₂ monomer structure, which might help in explaining their reported amyloid inhibition properties.