The initial stage of structural transformation of Aß42 peptides from the human and mole rat in the presence of Fe2+ and Fe3+: Related to Alzheimer's disease.

The early stage of secondary structural conversion of amyloid beta (Aß) to misfolded aggregations is a key feature of Alzheimer's disease (AD). Under normal physiological conditions, Aß peptides can protect neurons from the toxicity of highly concentrated metals. However, they become toxic under certain conditions. Under conditions of excess iron, amyloid precursor proteins (APP) become overexpressed. This subsequently increases Aß production. Experimental studies suggest that Aß fibrillation (main-pathway) and amorphous (off-pathway) aggregate formations are two competitive pathways driven by factors such as metal binding, pH and temperature. In this study, we performed molecular dynamic (MD) simulations to examine the initial stage of conformational transformations of human Aß (hAß) and rat Aß (rAß) peptides in the presence of Fe2+ and Fe3+ ions. Our results demonstrated that Fe2+ and Fe3+ play key roles in Aßs folding and aggregation. Fe3+ had a greater effect than Fe2+on Aßs' folding during intermolecular interactions and subsequently, had a greater effect in decreasing structural diversity. Fe2+ was observed to be more likely than Fe3+ to interact with nitrogen atoms from the residues of imidazole rings of His. rAß peptides are more energetically favorable than hAß for intermolecular interactions and amorphous aggregations. We concluded that most hAß structures were energetically unfavorable. However, hAßs with intermolecular ß-sheet formations in the C-terminal were energetically favorable. It is notable that Fe2+ can change the surface charge of hAß. Furthermore, Fe3+ can promote C-terminal folding by binding to Glu22 and Ala42, and by forming stable ß-sheet formations on the C-terminal. Fe3+ can also pause the main-pathway by inducing random aggregations.