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.

Automated summary

It has been found that two additional C-terminal residues in Aβ42 play a significant role in its faster aggregation compared to Aβ40. Through molecular dynamics simulations, a key residue, Arg5, was identified for the dimerization process of Aβ42. Amino acid substitutions of Arg5 were found to remarkably suppress the aggregation of both Aβ42 and Aβ40. Therefore, the two additional C-terminal residues alter the role of Arg5 in the oligomerization process.