Distinct Dimerization\nfor Various Alloforms of the Amyloid-Beta Protein: Aβ_1–40, Aβ_1–42, and Aβ_1–40(D23N)

Abstract

The Amyloid-beta protein is related to Alzheimer’s\ndisease, and various experiments have shown that oligomers as small\nas the dimer are cytotoxic. Two alloforms are mainly produced: Aβ_1–40 and Aβ_1–42. They have very\ndifferent oligomer distributions, and it was recently suggested, from\nexperimental studies, that this variation may originate from structural\ndifferences in their dimer structures. Little structural information\nis available on the Aβ dimer, however, and to complement experimental\nobservations, we simulated the folding of the wild-type Aβ_1–40 and Aβ_1–42 dimers as well\nas the mutated Aβ_1–40(D23N) dimer using an\naccurate coarse-grained force field coupled to Hamiltonian-temperature\nreplica exchange molecular dynamics. The D23N variant impedes the\nsalt-bridge formation between D23 and K28 seen in the wild-type Aβ,\nleading to very different fibrillation properties and final amyloid\nfibrils. Our results show that the Aβ_1–42 dimer\nhas a higher propensity than the Aβ_1–40 dimer\nto form β-strands at the central hydrophobic core (residues\n17–21) and at the C-terminal (residues 30–42), which\nare two segments crucial to the oligomerization of Aβ. The free\nenergy landscape of the Aβ_1–42 dimer is also\nbroader and more complex than that of the Aβ_1–40 dimer. Interestingly, D23N also impacts the free energy landscape\nby increasing the population of configurations with higher β-strand\npropensities when compared against Aβ₄₀. In addition,\nwhile Aβ_1–40(D23N) displays a higher β-strand\npropensity at the C-terminal, its solvent accessibility does not change\nwith respect to the wild-type sequence. Overall, our results show\nthe strong impact of the two amino acids Ile41-Ala42 and the salt-bridge\nD23–K28 on the folding of the Aβ dimer.