{"title":"通过计算研究 Aβ 和 hIAPP 之间的共聚和交叉播种,为阿尔茨海默病和 2 型糖尿病中的交叉对话提供基础。","authors":"Xinjie Fan, Xiaohan Zhang, Jiajia Yan, Huan Xu, Wenhui Zhao, Feng Ding*, Fengjuan Huang* and Yunxiang Sun*, ","doi":"10.1021/acs.jcim.4c00859","DOIUrl":null,"url":null,"abstract":"<p >The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer’s disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aβ and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aβ (Aβ<sub>10–21</sub> and Aβ<sub>30–41</sub>) and hIAPP (hIAPP<sub>8–20</sub> and hIAPP<sub>22–29</sub>), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of β-sheet-rich heterocomplexes, including potentially toxic β-barrel oligomers. The formation of Aβ and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aβ and hIAPP fibrils could mutually act as seeds, assisting each other’s monomers in converting into β-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aβ and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the β-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.</p>","PeriodicalId":44,"journal":{"name":"Journal of Chemical Information and Modeling ","volume":null,"pages":null},"PeriodicalIF":5.6000,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer’s Disease and Type 2 Diabetes\",\"authors\":\"Xinjie Fan, Xiaohan Zhang, Jiajia Yan, Huan Xu, Wenhui Zhao, Feng Ding*, Fengjuan Huang* and Yunxiang Sun*, \",\"doi\":\"10.1021/acs.jcim.4c00859\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer’s disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aβ and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aβ (Aβ<sub>10–21</sub> and Aβ<sub>30–41</sub>) and hIAPP (hIAPP<sub>8–20</sub> and hIAPP<sub>22–29</sub>), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of β-sheet-rich heterocomplexes, including potentially toxic β-barrel oligomers. The formation of Aβ and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aβ and hIAPP fibrils could mutually act as seeds, assisting each other’s monomers in converting into β-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aβ and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the β-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.</p>\",\"PeriodicalId\":44,\"journal\":{\"name\":\"Journal of Chemical Information and Modeling \",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2024-06-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Chemical Information and Modeling \",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jcim.4c00859\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Chemical Information and Modeling ","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jcim.4c00859","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Computational Investigation of Coaggregation and Cross-Seeding between Aβ and hIAPP Underpinning the Cross-Talk in Alzheimer’s Disease and Type 2 Diabetes
The coexistence of amyloid-β (Aβ) and human islet amyloid polypeptide (hIAPP) in the brain and pancreas is associated with an increased risk of Alzheimer’s disease (AD) and type 2 diabetes (T2D) due to their coaggregation and cross-seeding. Despite this, the molecular mechanisms underlying their interaction remain elusive. Here, we systematically investigated the cross-talk between Aβ and hIAPP using atomistic discrete molecular dynamics (DMD) simulations. Our results revealed that the amyloidogenic core regions of both Aβ (Aβ10–21 and Aβ30–41) and hIAPP (hIAPP8–20 and hIAPP22–29), driving their self-aggregation, also exhibited a strong tendency for cross-interaction. This propensity led to the formation of β-sheet-rich heterocomplexes, including potentially toxic β-barrel oligomers. The formation of Aβ and hIAPP heteroaggregates did not impede the recruitment of additional peptides to grow into larger aggregates. Our cross-seeding simulations demonstrated that both Aβ and hIAPP fibrils could mutually act as seeds, assisting each other’s monomers in converting into β-sheets at the exposed fibril elongation ends. The amyloidogenic core regions of Aβ and hIAPP, in both oligomeric and fibrillar states, exhibited the ability to recruit isolated peptides, thereby extending the β-sheet edges, with limited sensitivity to the amino acid sequence. These findings suggest that targeting these regions by capping them with amyloid-resistant peptide drugs may hold potential as a therapeutic approach for addressing AD, T2D, and their copathologies.
期刊介绍:
The Journal of Chemical Information and Modeling publishes papers reporting new methodology and/or important applications in the fields of chemical informatics and molecular modeling. Specific topics include the representation and computer-based searching of chemical databases, molecular modeling, computer-aided molecular design of new materials, catalysts, or ligands, development of new computational methods or efficient algorithms for chemical software, and biopharmaceutical chemistry including analyses of biological activity and other issues related to drug discovery.
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