Study of the conformational transition in amyloidogenic peptides

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. I have collaborated to study the transition from ideal α-helix to ß-hairpin conformation by long time scale, all atoms molecular dynamics simulations in explicit water solvent [1]. Two amyloidogenic peptides have been investigated: the H1 peptide from prion protein and the Aß(12-28) fragment from the Aß(1-42) peptide responsible for Alzheimer disease.


Figure 1: Summary of the structural behaviour of the H1 peptide from Prion Protein.


Figure 2: Experimental data available (before 2004) on the peptide H1.


Figure 3: Summary of the MD simulations of the H1 peptide.

The MD simulation starting from the low-resolution X-ray structure (see Figure I) is reported in Figure 4. A stable beta-haiprin is formed within 8 ns.


Figure 4.  MD simulation at 300 K starting from the low-resolution X-ray structure. The beta’-hairpin is formed at t = 8 ns.

The simulations evidence the unfolding of α-helix, followed by the formation of bent conformations and a final convergence to ordered in register ß-hairpin conformations (see Figure 4).


Figure 4. Top. Time evolution of the H1 peptide secondary structure. The analysis was performed with the DSSP program. MD simulation at 300 K starting from an ideal ’-helix. Note the formation of the beta’-hairpin at t = 408 ns. Bottom. The starting and final structures of each simulation are shown on the left and right sides, respectively.

The ß-hairpins observed, despite different sequences, exhibit a common dynamic behaviour and the presence of a particular 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 ß-hairpin structures.

Furthermore, the simulations presented herein evidence the stabilization of the Alpha-helical conformations induced by the presence of an organic fluorinated co-solvent.


Figure I.  MD simulation at 300 K starting from H1 in ideal alpha-helix in 30% TFE. The alpha-helix structure remains mainly preserved as from the experiments.

The results of molecular dynamics in 2,2,2-trifluoroethanol (TFE)/water mixture provide a further evidence that the peptide coating effect of TFE molecules is responsible for the stabilization of the soluble helical conformation.


  1. Daidone, F. Simona, Roccatano, R. A. Broglia, G. Tiana, G. Colombo, A. Di Nola. β-hairpin conformation of fibrillogenic peptides: structure and α/β transition revealed by molecular dynamics simulations. PROTEINS: Struct., Funct. and Bioinf., 57, 198-204 (2004).

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