TY - JOUR KW - Computer Simulation KW - Models, Molecular KW - Protein Structure, Secondary KW - Humans KW - Amino Acid Sequence KW - Molecular Sequence Data KW - Amyloid KW - Peptide Fragments KW - Prions KW - Molecular Conformation KW - Fungal Proteins KW - Saccharomyces cerevisiae Proteins KW - Point Mutation KW - Amyloid beta-Peptides KW - Glutathione Peroxidase KW - Islet Amyloid Polypeptide KW - Sequence Alignment AU - M. Cecchini AU - R. Curcio AU - M. Pappalardo AU - R. Melki AU - A. Caflisch AB -

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.

BT - Journal of Molecular Biology C1 - 0076 DA - 2006 Apr 7 DO - 10.1016/j.jmb.2006.01.009 IS - 4 J2 - J. Mol. Biol. LA - eng M3 - Research Article N2 -

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.

PY - 2006 SP - 1306 EP - 1321 T2 - Journal of Molecular Biology TI - A molecular dynamics approach to the structural characterization of amyloid aggregation VL - 357 SN - 0022-2836 ER -