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Hundreds of millions of people around the world have been affected by Type 2 diabetes (T2D) which is a metabolic disorder. Clinical research has revealed T2D as a possible risk factor for Alzheimer’s disease (AD) development (and vice versa). Amyloid-β (Aβ) and human islet amyloid polypeptide are the main pathological species in AD and T2D, respectively. However, the mechanisms by which these two amyloidogenic peptides co-aggregate are largely uninvestigated. Herein, for the first time, we present the cross-seeding between Amylin1-37 and Aβ40 considering the particular effect of the histidine tautomerism at atomic resolution applying the all-atom molecular dynamics (MD) simulations for heterodimeric complexes. The results via random seed MD simulations indicated that the Aβ40(δδδ) isomer in cross-talking with Islet(ε) and Islet(δ) isomers could retain or increase the β-sheet content in its structure that may make it more prone to further aggregation and exhibit higher toxicity. The other tautomeric isomers which initially did not have a β-sheet structure in their monomeric forms did not show any generated β-sheet, except for one seed of the Islet(ε) and Aβ40(εεε) heterodimers complex that displayed a small amount of formed β-sheet. This computational research may provide a different point of view to examine all possible parameters that may contribute to the development of AD and T2D and provide a better understanding of the pathological link between these two severe diseases.

international journal of molecular sciences

Mechanistic Insights into the Polymorphic Associations and Cross-Seeding of Aβ and hIAPP in the Presence of Histidine Tautomerism: An All-Atom Molecular Dynamic Study