Critical Nucleus Structure and Aggregation Mechanism of the C-terminal Fragment of Copper–Zinc Superoxide Dismutase Protein

详细信息    查看全文

• 作者：Yu Zou ; Yunxiang Sun ; Yuzhen Zhu ; Buyong Ma ; Ruth Nussinov ; Qingwen Zhang
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：March 16, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：286-296
• 全文大小：645K
• ISSN：1948-7193

文摘

The aggregation of the copper–zinc superoxide dismutase (SOD1) protein is linked to familial amyotrophic lateral sclerosis, a progressive neurodegenerative disease. A recent experimental study has shown that the ¹⁴⁷GVIGIAQ¹⁵³ SOD1 C-terminal segment not only forms amyloid fibrils in isolation but also accelerates the aggregation of full-length SOD1, while substitution of isoleucine at site 149 by proline blocks its fibril formation. Amyloid formation is a nucleation–polymerization process. In this study, we investigated the oligomerization and the nucleus structure of this heptapeptide. By performing extensive replica-exchange molecular dynamics (REMD) simulations and conventional MD simulations, we found that the GVIGIAQ hexamers can adopt highly ordered bilayer β-sheets and β-barrels. In contrast, substitution of I149 by proline significantly reduces the β-sheet probability and results in the disappearance of bilayer β-sheet structures and the increase of disordered hexamers. We identified mixed parallel–antiparallel bilayer β-sheets in both REMD and conventional MD simulations and provided the conformational transition from the experimentally observed parallel bilayer sheets to the mixed parallel–antiparallel bilayer β-sheets. Our simulations suggest that the critical nucleus consists of six peptide chains and two additional peptide chains strongly stabilize this critical nucleus. The stabilized octamer is able to recruit additional random peptides into the β-sheet. Therefore, our simulations provide insights into the critical nucleus formation and the smallest stable nucleus of the ¹⁴⁷GVIGIAQ¹⁵³ peptide.