An important feature of Alzheimer's disease is that the toxic species of the amyloid-p protein (Ati) might be both soluble oligomers and insoluble fibrils. This finding makes Abeta oligomers attractive therapeutic targets. A second feature is that small peptides as short as 4, 7, 8 and 15 amino acids can also form amyloid fibrils, rendering the analysis of the early steps of Ap aggregation more tractable by molecular modelling studies. In this work, we simulate the folding of a dimer and a trimer of the fragment AP16-22 using the activation-relaxation technique and a simplified energy model. Starting from randomly chosen configurations, our sampling procedure, which is not biased towards a specific intra- and inter-molecular arrangement, leads to an in register, antiparallel p-sheet organization in agreement with solid state NMR. Analysis of the trajectories allows to characterize the oligomeric intermediates in atomic detail. We find that occurrence of an intermediate containing 30% ohelix is not an obligatory step for folding A016-22 in its dimeric and trimeric forms. This indicates that there are alternative folding pathways for fibril formation of the Abeta1-42 and Ap1-40 peptides.
展开▼
