Polymorphic Associations and Structures of the Cross-Seeding of A尾1鈥?2 and hIAPP1鈥?7 Polypeptides
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- 作者：Mingzhen Zhang ; Rundong Hu ; Hong Chen ; Xiong Gong ; Feimeng Zhou ; Li Zhang ; Jie Zheng
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2015
- 出版时间：August 24, 2015
- 年：2015
- 卷：55
- 期：8
- 页码：1628-1639
- 全文大小：657K
- ISSN：1549-960X
文摘
Emerging evidence have shown that the patients with Alzheimer鈥檚 disease (AD) often have a higher risk of later developing type II diabetes (T2D), and vice versa, suggesting a potential pathological link between AD and T2D. Amyloid-尾 (A尾) and human islet amyloid polypeptide (hIAPP) are the principle causative components responsible for the pathologies of AD and T2D, respectively. The cross-sequence interactions between A尾 and hIAPP may provide a molecular basis for better understanding the potential link between AD and T2D. Herein, we systematically modeled and simulated the cross-sequence aggregation process, molecular interactions, and polymorphic structures of full-length A尾 and hIAPP peptides using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD) and all-atom molecular dynamics (MD) simulations, with particular focus on the effect of association models between A尾 and hIAPP on the structural stability and polymorphic populations of hybrid A尾鈥揾IAPP aggregates. Four distinct association models (double-layer, elongation, tail鈥搕ail, and block models) between A尾 and hIAPP oligomers were identified, and the associated polymorphic A尾鈥揾IAPP structures were determined as well. Among them, different association models led to different A尾鈥揾IAPP aggregates, with large differences in structural morphologies and populations, interacting interfaces, and underlying association forces. The computational models support the cross-sequence interactions between A尾 and hIAPP pentamers, which would lead to the complex hybrid A尾鈥揾IAPP assemblies. This computational work may also provide a different point of view to a better understanding of a potential link between AD and T2D.