富含丙氨酸的β-折叠寡聚体的分子动力学模拟：对淀粉样蛋白形成的见解。
Molecular dynamics simulations of alanine rich beta-sheet oligomers: Insight into amyloid formation.
作者信息
Ma Buyong, Nussinov Ruth
机构信息
Laboratory of Experimental and Computational Biology, National Cancer Institute at Frederick, Maryland 21702, USA.
出版信息
Protein Sci. 2002 Oct;11(10):2335-50. doi: 10.1110/ps.4270102.
The aggregation observed in protein conformational diseases is the outcome of significant new beta-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.
在蛋白质构象疾病中观察到的聚集现象是天然状态下不存在的显著新β-折叠结构的结果。肽模型系统在原纤维聚集体形成的研究中很有用。实验发现，短肽AGAAAAGA是淀粉样变性最强的肽之一。该肽对应于叙利亚仓鼠朊病毒蛋白（ShPrP）的113-120位残基。在所有已确定PrP序列的物种中都观察到该肽是保守的。我们通过分子动力学模拟研究了寡聚体AGAAAAGA和AAAAAAAA（A8）的稳定性。当AGAAAAGA和AAAAAAAA的寡聚体大小为6至8（六聚体至八聚体）时，发现它们是稳定的。随后在A8-八聚体表面放置一个额外的α-螺旋AAAAAAA的模拟揭示了与构象变化和寡聚体生长相关的分子事件。我们的研究探讨了聚集体种子的最小寡聚体大小和种子生长机制。我们对朊病毒衍生的8个残基淀粉样变性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作用。
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