Molecular dynamics studies of alpha-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 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.
Nordling
Erik
E
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, 171 77, Sweden. erik.nordling@biovitrum.com
Kallberg
Yvonne
Y
Johansson
Jan
J
Persson
Bengt
B
D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary
D010455:Peptides