A molecular dynamics approach to the structural characterization of amyloid aggregation

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 (Ure2p_1-94) and to design a double-point mutant (Ure2p-N4748S_1-94) with lower β-aggregation propensity. The change in the aggregation propensity of Ure2p-N4748S_1-94 is verified in vitro using the thioflavin T binding assay.

0076