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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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