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 (A?) 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 A? variants, i.e. A2T and A2V, in the heterozygous state. The mixture of A2V A?1-6 (A?₆) hexapeptide and WT A?1-42 (??₄₂) is also found neuroprotective. Motivated by these findings, in this study we investigate the effects of WT, A2V, and A2T A?₆ hexapeptide binding on the monomeric WT A?₄₂ landscape. For this purpose, we have performed extensive atomistic Replica Exchange Molecular Dynamics simulations, elucidating preferential binding of A?₄₂ with the A2V and A2T hexapeptides compared to WT A?₆. A notable reorganization of the A?₄₂ landscape is revealed due to hexapeptide association, as manifested by lowering of transient interactions between the central and C-terminal hydrophobic patches. Concurrently, A?₆-bound A?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 A?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 A?₄₂ monomer structure, which might help in explaining their reported amyloid inhibition properties.

SUBMITTER: Chakraborty S 

PROVIDER: S-EPMC5577341 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature