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M. Cecchini; R. Curcio; M. Pappalardo; R. Melki; A. Caflisch

Journal: J. Mol. Biol.
Year: 2006
Volume: 357
Issue: 4
Pages: 1306-1321
DOI: 10.1016/j.jmb.2006.01.009
Type of Publication: Journal Article

Amino Acid Sequence; Amyloid; Amyloid beta-Peptides; Computer Simulation; Fungal Proteins; Glutathione Peroxidase; Humans; Islet Amyloid Polypeptide; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Peptide Fragments; Point Mutation; Prions; Protein Structure, Secondary; Saccharomyces cerevisiae Proteins; Sequence Alignment


A novel computational approach to the structural analysis of ordered β-aggregation is presented and validated on three known amyloidogenic polypeptides. The strategy is based on the decomposition of the sequence into overlapping stretches and equilibrium implicit solvent molecular dynamics (MD) simulations of an oligomeric system for each stretch. The structural stability of the in-register parallel aggregates sampled in the implicit solvent runs is further evaluated using explicit water simulations for a subset of the stretches. The beta-aggregation propensity along the sequence of the Alzheimer's amyloid-β peptide (Aβ42) is found to be highly heterogeneous with a maximum in the segment V12HHQKLVFFAE22 and minima at S8G9, G25S26, G29A30, and G38V39, which are turn-like segments. The simulation results suggest that these sites may play a crucial role in determining the aggregation tendency and the fibrillar structure of Aβ42. Similar findings are obtained for the human amylin, a 37-residue peptide that displays a maximal β-aggregation propensity at Q10RLANFLVHSSNN22 and two turn-like sites at G24A25 and G33S34. In the third application, the MD approach is used to identify β-aggregation "hot-spots" within the N-terminal domain of the yeast prion Ure2p (Ure2p1-94) and to design a double-point mutant (Ure2p-N4748S1-94) with lower β-aggregation propensity. The change in the aggregation propensity of Ure2p-N4748S1-94 is verified in vitro using the thioflavin T binding assay.