Key Residue for Aggregation of Amyloid-β Peptides.

It is known that oligomers of amyloid-β (Aβ) peptide are associated with Alzheimer's disease. Aβ has two isoforms: Aβ40 and Aβ42. Although the difference between Aβ40 and Aβ42 is only two additional C-terminal residues, Aβ42 aggregates much faster than Aβ40. It is unknown what role the C-terminal two residues play in accelerating aggregation. Since Aβ42 is more toxic than Aβ40, its oligomerization process needs to be clarified. Moreover, clarifying the differences between the oligomerization processes of Aβ40 and Aβ42 is essential to elucidate the key factors of oligomerization. Therefore, to investigate the dimerization process, which is the early oligomerization process, Hamiltonian replica-permutation molecular dynamics simulations were performed for Aβ40 and Aβ42. We identified a key residue, Arg5, for the Aβ42 dimerization. The two additional residues in Aβ42 allow the C-terminus to form contact with Arg5 because of the electrostatic attraction between them, and this contact stabilizes the β-hairpin. This β-hairpin promotes dimer formation through the intermolecular β-bridges. Thus, we examined the effects of amino acid substitutions of Arg5, thereby confirming that the mutations remarkably suppressed the aggregation of Aβ42. Moreover, the mutations of Arg5 suppressed the Aβ40 aggregation. It was found by analyzing the simulations that Arg5 is important for Aβ40 to form intermolecular contacts. Thus, it was clarified that the role of Arg5 in the oligomerization process varies due to the two additional C-terminal residues.