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

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 (Aβ(6)) hexapeptide and WT Aβ1–42 (Αβ(42)) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T Aβ(6) hexapeptide binding on the monomeric WT Aβ(42) landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of Aβ(42) with the A2V and A2T hexapeptides compared to WT Aβ(6). A notable reorganization of the Aβ(42) landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, Aβ(6)-bound Aβ(42) 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 Aβ(42) 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 Aβ(42) monomer structure, which might help in explaining their reported amyloid inhibition properties.