β-Hairpin conformation of fibrillogenic peptides: Structure and a-β transition mechanism revealed by molecular dynamics simulations

Isabella Daidone ¹, Fabio Simona ², Danilo Roccatano ³, Ricardo A. Broglia ⁴, Guido Tiana ⁴, Giorgio Colombo ², Alfredo Di Nola ^{1 *}

¹Department of Chemistry, University of Rome La Sapienza, Rome, Italy
²Istituto di Chimica del Riconoscimento Molecolare, CNR, Milano, Italy
³School of Engineering and Science, International University Bremen, Bremen, Germany
⁴Department of Physics, University of Milano, Milano, Italy

email: Alfredo Di Nola (dinola@degas.chem.uniroma1.it)

^*Correspondence to Alfredo Di Nola, Department of Chemistry, University of Rome La Sapienza, P. le A. Moro 5, Rome 00185 Italy

FULL TEXT

Funded by:
European Community Training and Mobility of Researchers Program Protein (Mis)-Folding
Italian National Research Council

Keywords

misfolding - prion protein - Abeta peptide - amyloid diseases alpha-to-beta conformational transition

Abstract

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 alpha-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 alpha-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 alpha-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.