The initial stage of structural transformation of Aβ42 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 (A beta) to misfolded aggregations is a key feature of Alzheimer's disease (AD). Under normal physiological conditions, A beta 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 A beta production. Experimental studies suggest that A beta 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 A beta (hA beta) and rat A beta (rA beta) peptides in the presence of Fe2+ and Fe3+ ions. Our results demonstrated that Fe2+ and Fe3+ play key roles in ADDS folding and aggregation. Fe(3+ )had a greater effect than Fe2+ on A beta s' 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. rA beta peptides are more energetically favorable than hA beta for intermolecular interactions and amorphous aggregations. We concluded that most hA beta structures were energetically unfavorable. However, hA beta s with intermolecular beta-sheet formations in the C-terminal were energetically favorable. It is notable that Fe2+ can change the surface charge of hA beta. Furthermore, Fe3+ can promote C-terminal folding by binding to Glu22 and Ala42, and by forming stable beta-sheet formations on the C-terminal. Fe3+ can also pause the main-pathway by inducing random aggregations.