Molecular dynamics studies of α-helix stability in fibril-forming peptides

Diseases associated with protein fibril-formation, such as the prion diseases and Alzheimer’s disease, are gaining increased attention due to their medical importance and complex origins. Using molecular dynamics (MD) simulations in an aqueous environment, we have studied the stability of the α-helix covering positions 15–25 of the amyloid β-peptide (Aβ) involved in Alzheimer’s disease. The effects of residue replacements, including the effects of Aβ disease related mutations, were also investigated. The MD simulations show a very early (2 ns) loss of α-helical structure for the Flemish (Aβ(A21G)), Italian (Aβ(E22K)), and Iowa (Aβ(D23N)) forms associated with hereditary Alzheimer’s disease. Similarly, an early (5 ns) loss of α-helical structure was observed for the Dutch (Aβ(E22Q)) variant. MD here provides a possible explanation for the structural changes. Two variants of Aβ, Aβ(K16A,L17A,F20A) and Aβ(V18A,F19A,F20A), that do not produce fibrils in vitro were also investigated. The Aβ(V18A,F19A,F20A) initially loses its helical conformation but refolds into helix several times and spends most of the simulation time in helical conformation. However, the Aβ(K16A,L17A,F20A) loses the α-helical structure after 5 ns and does not refold. For the wildtype Aβ(1–40) and Aβ(1–42), the helical conformation is lost after 5 ns or after 40 ns, respectively, while for the “familial” (Aβ(A42T)) variant, the MD simulations suggest that a C-terminal β-strand is stabilised, which could explain the fibrillation. The simulations for the Arctic (Aβ(E22G)) variant indicate that the α-helix is kept for 2 ns, but reappears 2 ns later, whereafter it disappears after 10 ns. The MD results are in several cases compatible with known experimental data, but the correlation is not perfect, indicating that multimerisation tendency and other factors might also be important for fibril formation.