beta-hairpin conformation of fibrillogenic peptides: Structure and alpha-beta transition mechanism revealed by molecular dynamics simulations

Understanding the conformational. transitions that trigger the
aggregation and amyloidogenesis of otherwise soluble peptides at atomic
resolution is of fundamental relevance for the design of effective
therapeutic agents against amyloid-related disorders. In the present
study the transition from ideal a-helical to beta-hairpin conformations
is revealed by long timescale molecular dynamics simulations in explicit
water solvent, for two well-known amyloidogenic peptides: the H1 peptide
from prion protein and the Abeta(12-28) fragment from the Abeta(1-42)
peptide responsible for Alzheimer's disease. The simulations highlight
the unfolding of a-helices, followed by the formation of bent
conformations and a final convergence to ordered in register
beta-hairpin conformations. The beta-hairpins observed, despite
different sequences, exhibit a common dynamic behavior and the presence
of a peculiar pattern of the hydrophobic side-chains, in particular in
the region of the turns. These observations hint at a possible common
aggregation mechanism for the onset of different amyloid diseases and a
common mechanism in the transition to the beta-hairpin structures.
Furthermore the simulations presented herein evidence the stabilization
of the a-helical conformations induced by the presence of an organic
fluorinated cosolvent. The results of MD simulation in
2,2,2-trifluoroethanol (TFE)/water mixture provide further evidence that
the peptide coating effect of TFE molecules is responsible for the
stabilization of the soluble helical conformation. (C) 2004 Wiley-Liss,
Inc.