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Abstract

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 alpha-helix covering positions 15-25 of the amyloid beta-peptide (A beta) involved in Alzheimer's disease. The effects of residue replacements, including the effects of A beta disease related mutations, were also investigated. The MD simulations show a very early (2 ns) loss of alpha-helical structure for the Flemish (A beta(A21G)), Italian (A beta(E22K)), and Iowa (A beta(D23N)) forms associated with hereditary Alzheimer's disease. Similarly, an early (5 ns) loss of alpha-helical structure was observed for the Dutch (A beta(E22Q)) variant. MD here provides a possible explanation for the structural changes. Two variants of A beta, A beta(K16A,L17A,F20A) and A beta(V18A,F19A,F20A), that do not produce fibrils in vitro were also investigated. The A beta(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 A beta(K16A,L17A,F20A) loses the alpha-helical structure after 5 ns and does not refold. For the wildtype A beta(1-40) and A beta(1-42), the helical conformation is lost after 5 ns or after 40 ns, respectively, while for the "familial" (A beta(A42T)) variant, the MD simulations suggest that a C-terminal beta-strand is stabilised, which could explain the fibrillation. The simulations for the Arctic (A beta(E22G)) variant indicate that the alpha-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.

Keywords

amyloid beta-peptide; amyloid fibril; molecular dynamics; secondary structure

Published in

Journal of Computer-Aided Molecular Design
2008, volume: 22, number: 1, pages: 53-58

SLU Authors

UKÄ Subject classification

Animal and Dairy Science
Veterinary Science

Publication identifier

  • DOI: https://doi.org/10.1007/s10822-007-9155-6

Permanent link to this page (URI)

https://res.slu.se/id/publ/20786