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Oligomerization of FVFLM peptides and their ability to inhibit beta amyloid peptides aggregation: consideration as a possible model

机译：FVFLM肽的低聚及其抑制β淀粉样肽聚集的能力：考虑作为一种可能的模型

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Preeclampsia, a pregnancy-specific disorder, shares typical pathophysiological features with protein misfolding disorders including Alzheimer’s disease. Characteristic for preeclampsia is the involvement of multiple proteins of which fragments of SERPINA1 and β-amyloid co-aggregate in urine and placenta of preeclamptic women. To explore the biophysical basis of this interaction, we investigated the multidimensional efficacy of the FVFLM sequence in SERPINA1, as a model inhibitory agent of β-amyloid aggregation. After studying the oligomerization of FVFLM peptides using all-atom molecular dynamics simulations with the GROMOS43a1 force field and explicit water, we report that FVFLM can aggregate and its aggregation is spontaneous with a remarkably faster rate than that recorded for KLVFF (aggregation “hot-spot” from β-amyloid). The fast kinetics of FVFLM aggregation was found to be driven primarily by core-like aromatic interactions originating from the anti-parallel orientation of complementarily uncharged strands. The conspicuously stable aggregation mechanism observed for FVFLM peptides is found not to conform to the popular 'dock-lock' scheme. We also found high propensity of FVFLM for KLVFF binding. When present, FVFLM disrupts the β-amyloid aggregation pathway and we propose that FVFLM-like peptides might be used to prevent the assembly of full-length Aβ or other pro-amyloidogenic peptides into amyloid fibrils
机译：子痫前期是一种特定于妊娠的疾病，与包括阿尔茨海默氏病在内的蛋白质错误折叠疾病具有典型的病理生理特征。子痫前期的特征是涉及多种蛋白质，其中SERPINA1和β-淀粉样蛋白的片段在子痫前期妇女的尿液和胎盘中共同聚集。为了探索这种相互作用的生物物理基础，我们研究了SERPINA1中FVFLM序列作为β-淀粉样蛋白聚集的模型抑制剂的多维功效。在使用GROMOS43a1力场和显性水通过全原子分子动力学模拟研究了FVFLM肽的寡聚之后，我们报告FVFLM可以自发聚集，其聚集速度比KLVFF记录的快得多（聚集“热点”来自β-淀粉样蛋白）。发现FVFLM聚集的快速动力学主要是由互补的不带电链的反平行方向起源的核样芳香相互作用所驱动。发现对FVFLM肽观察到的明显稳定的聚集机制不符合流行的“ dock-lock”方案。我们还发现FVFLM倾向于KLVFF结合。当存在FVFLM时，它会破坏β-淀粉样蛋白的聚集途径，我们建议使用FVFLM-like肽来防止全长Aβ或其他促淀粉样蛋白的肽组装成淀粉样原纤维。

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