Mechanism for the α-helix to β-hairpin transition

The aggregation of α-helix-rich proteins into β-sheet-rich amyloid fibrils is associated with fatal diseases, such as Alzheimer's disease and prion disease. During an aggregation process, protein secondary structure elements-α-helices-undergo conformational changes to α-sheets. The fact that proteins with different sequences and structures undergo a similar transition on aggregation suggests that the sequence nonspecific hydrogen bond interaction among protein backbones is an important factor. We perform molecular dynamics simulations of a polyalanine model, which is an α-helix in its native state and observe a metastable β-hairpin intermediate. Although a β-hairpin has larger potential energy than an α-helix, the entropy of a β-hairpin is larger because of fewer constraints imposed by the hydrogen bonds. In the vicinity of the transition temperature, we observe the interconversion of the α-helix and β-sheet states via a random coil state. We also study the effect of the environment by varying the relative strength of side-chain interactions for a designed peptide-an α-helix in its native state. For a certain range of side-chain interaction strengths, we find that the intermediate β-hairpin state is destabilized and even disappears, suggesting an important role of the environment in the aggregation propensity of a peptide.