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β‐Hairpin conformation of fibrillogenic peptides: Structure and α‐β 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 α‐helical to β‐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 Aβ(12–28) fragment from the Aβ(1–42) peptide responsible for Alzheimer's disease. The simulations highlight the unfolding of α‐helices, followed by the formation of bent conformations and a final convergence to ordered in register β‐hairpin conformations. The β‐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 β‐hairpin structures. Furthermore the simulations presented herein evidence the stabilization of the α‐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. Proteins 2004. © 2004 Wiley‐Liss, Inc.