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Medin淀粉样蛋白的聚集导致动脉壁退化和脑血管功能障碍，参与多种血管疾病的发生与发展。在血管性痴呆或阿尔茨海默症患者的脑小动脉中发现Medin聚集体增加，且Medin与血管β-淀粉样蛋白(Aβ)沉积物共定位。实验证实Medin通过与Aβ形成异源纤维并交叉接种Aβ而直接与Aβ产生作用并促进其聚集。然而，Medin与Aβ共聚集的微观机制仍不清楚。本文利用大规模的全原子副本交换分子动力学模拟(累计模拟时间72 µs)，对Aβ42与Medin三聚体在不同多肽环境(即自聚集vs.共聚集)的相互作用及构象分布进行了研究。结果表明，Aβ42与Medin的亲和力更高，Aβ42与Medin在自身或彼此结合时具有相似的分子识别位点或区域，为共聚集提供基础。Aβ42的N端与Medin的C端在Aβ42-Medin交叉聚集中起到关键作用。更重要的是，共聚集显著改变了Aβ42与Medin的相互作用强度、方式以及结构特征。Aβ42-Medin三聚体中，Aβ42分子间相互作用减弱，仅保留疏水核心区域(16KLVFFA21)之间的结合而提高其他区域的自由度； Medin形成更多的β结构与更少的helix结构，但Aβ42却形成更多的helix与更少的β；而Medin中高β倾向性区域向肽链中部和C端迁移，表明Medin可能通过C端形成β结构作为核心从而驱动其与Aβ42的协同聚集。本工作在原子水平上详尽地阐明了共聚集对Aβ42与Medin相互作用与结构特征的影响，为理解Aβ42-Medin共聚集分子机制以及不同疾病之间交叉关联的病理机制提供了有益见解。The aggregation of Medin is closely associated with the arterial wall degeneration and cerebrovascular dysfunction. Medin aggregates are increased in cerebral arterioles of patients with vascular dementia or Alzheimer’s disease, and medin co-localizes with vascular amyloid-β (Aβ) deposits. Previous study demonstrated that Medin interacts directly with Aβ, forming heterologous fibrils with Aβ and promoting Aβ aggregation. However, the underlying mechanism of the co-aggregation between Medin and Aβ remains largely elusive. Here, we explored the interactions and conformational ensembles of Aβ42/Medin trimers in different peptide environments (self-aggregation vs. co-aggregation) by performing allatom replica exchange molecular dynamic simulation on Aβ42/Medin homotrimers and Aβ42-Medin heterotrimer with an accumulated simulation time of 72 μs. Our results reveal that Aβ42 exhibits higher affinity with Medin, and both Aβ42 and Medin have similar molecular recognition sites for self-aggregation and co-aggregation. The N-terminus of Aβ42 and the C-terminus of Medin play critical roles in Aβ42-Medin cross-talk. More importantly, co-aggregation significantly alters the interaction strength, binding patterns and structural characteristics of Aβ42 and Medin. Intermolecular interactions of Aβ42 trimers are relatively weak among three trimers and the binding sites are concentrated between N- and N-termini, between N- and C-termini as well as between C- and C-termini of Aβ42. In contrast, intermolecular interactions of Medin trimers are strongest and the binding sites are widely and uniformly distributed in Medin peptides. Intermolecular interactions of Aβ42 in Aβ42-Medin heterotrimer are decreased compared with Aβ42 trimers, only the binding of the hydrophobic core regions (16KLVFFA21) is retained and other regions of Aβ42 gain increased flexibility. 2D free energy landscapes reveal distinct conformational diversities among the homo- and heterotrimers, with the order of diversity being Medin/Aβ42-Medin trimers > Aβ42 trimers. The Rg of Aβ42 trimers is smaller than that of the other two trimers, implying that Aβ42 trimers adopt a more compact structure, whereas Medin/Aβ42- Medin trimers exhibit a relatively loose conformation. Aβ42 trimers possess the highest β content whereas Medin trimers exhibit the lowest β probability. We find that Aβ42-Medin co-aggregation induces Medin to form more β-structures with longer length and fewer helices, while promotes Aβ42 to form more helices and fewer β-structures. High β- propensity regions of Medin in heterotrimers shift towards the C-terminus of Medin, suggesting that Medin utilize its C-terminal β region as a core motif to drive its co-aggregation with Aβ42. These results elucidate the detailed influences of co-aggregation on the interactions and conformations of Aβ42 and Medin. This work provides key insights into the molecular mechanism of Aβ42-Medin co-aggregation and the pathological cross-talk between related diseases.
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Keywords:
- peptide co-aggregation /
- amyloid-β /
- Medin /
- molecular dynamic simulations
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