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 (Aß) 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 Aß variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V Aß1-6 (Aß6) hexapeptide and WT Aß1-42 (Αß42) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T Aß6 hexapeptide binding on the monomeric WT Aß42 landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of Aß42 with the A2V and A2T hexapeptides compared to WT Aß6. A notable reorganization of the Aß42 landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, Aß6-bound Aß42 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 Aß42 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 Aß42 monomer structure, which might help in explaining their reported amyloid inhibition properties.