Key Residue for Aggregation of Amyloid-β Peptides

It is known that oligomers of amyloid-beta (A beta) peptide are associated with Alzheimer's disease. A beta has two isoforms: A beta 40 and A beta 42. Although the difference between A beta 40 and A beta 42 is only two additional C-terminal residues, A beta 42 aggregates much faster than A beta 40. It is unknown what role the C-terminal two residues play in accelerating aggregation. Since A beta 42 is more toxic than A beta 40, its oligomerization process needs to be clarified. Moreover, clarifying the differences between the oligomerization processes of A beta 40 and A beta 42 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 A beta 40 and A beta 42. We identified a key residue, Arg5, for the A beta 42 dimerization. The two additional residues in A beta 42 allow the C-terminus to form contact with Arg5 because of the electrostatic attraction between them, and this contact stabilizes the beta-hairpin. This beta-hairpin promotes dimer formation through the intermolecular beta-bridges. Thus, we examined the effects of amino acid substitutions of Arg5, thereby confirming that the mutations remarkably suppressed the aggregation of A beta 42. Moreover, the mutations of Arg5 suppressed the A beta 40 aggregation. It was found by analyzing the simulations that Arg5 is important for A beta 40 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.