Molecular dynamics simulations of alanine rich β-sheet oligomers:: Insight into amyloid formation
Molecular dynamics simulations of alanine rich β-sheet oligomers:: Insight into amyloid formation
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DOI：
10.1110/ps.4270102
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发表时间：
2002-10-01
期刊：
影响因子：
8
通讯作者：
Nussinov, R
中科院分区：
文献类型：
--
作者：
Ma, BY;Nussinov, R
在蛋白质构象疾病中观察到的聚集是在天然状态中不存在的重要的新P-sheet结构的结果。多肽模型系统在研究纤维聚集体形成方面非常有用。实验发现，短肽AGAAAAGA是淀粉样蛋白含量最高的肽之一。该肽对应叙利亚仓鼠朊蛋白（ShPrP）残基113-120。观察到该肽在所有已确定的PrP序列的物种中都是保守的。我们通过分子动力学模拟模拟了低聚物AGAAAAGA和AAAAAAAA （A8）的稳定性。AGAAAAGA和AAAAAAAA的低聚物在大小为6 ~ 8（六聚体到八聚体）时都是稳定的。随后对放置在a8 -八聚体表面的另一个α -螺旋AAAAAAAA的模拟揭示了与构象变化和低聚物生长相关的分子事件。我们的研究解决了聚集体种子的最小寡聚物大小和种子生长的机制。我们对朊病毒衍生的8-残基淀粉样蛋白肽及其变体的模拟表明，八聚体足够稳定，可以作为种子，并且稳定的驱动力是疏水效应。
The aggregation observed in protein conformational diseases is the outcome of significant new P-sheet structure not present in the native state. Peptide model systems have been useful in studies of fibril aggregate formation. Experimentally, it was found that a short peptide AGAAAAGA is one of the most highly amyloidogenic peptides. This peptide corresponds to the Syrian hamster prion protein (ShPrP) residues 113-120. The peptide was observed to be conserved in all species for which the PrP sequence has been determined. We have simulated the stabilities of oligomeric AGAAAAGA and AAAAAAAA (A8) by molecular dynamic simulations. Oligomers of both AGAAAAGA and AAAAAAAA were found to be stable when the size is 6 to 8 (hexamer to octamer). Subsequent simulation of an additional alpha-helical AAAAAAAA placed on the A8-octamer surface has revealed molecular events related to conformational change and oligomer growth. Our study addresses both the minimal oligomeric size of an aggregate seed and the mechanism of seed growth. Our simulations of the prion-derived 8-residue amyloidogenic peptide and its variant have indicated that an octamer is stable enough to be a seed and that the driving force for stabilization is the hydrophobic effect.