Mechanistic Insights into the Co-Aggregation of Aβ and hIAPP: An All-Atom Molecular Dynamic Study

Patients with Alzheimer’s disease (AD) have a high risk of developing Type II diabetes (T2D). The co-aggregation of the two disease-related proteins, Aβ and hIAPP, has been proposed as a potential molecular mechanism. However, the detailed Aβ–hIAPP interactions and structural characteristics of co-aggregates are mostly unknown at atomic level. Here, we explore the conformational ensembles of the Aβ–hIAPP heterodimer and Aβ or hIAPP homodimer by performing all-atom explicit-solvent replica exchange molecular dynamic simulations. Our simulations show that the interaction propensity of Aβ–hIAPP in the heterodimer is comparable with that of Aβ–Aβ/hIAPP–hIAPP in the homodimer. Similar hot spot residues of Aβ/hIAPP in the homodimer and heterodimer are identified, indicating that both Aβ and hIAPP have similar molecular recognition sites for self-aggregation and co-aggregation. Aβ in the heterodimer possesses three high β-sheet probability regions: the N-terminal region E3–H6, the central hydrophobic core region K16–E22, and the C-terminal hydrophobic region I31–A41, which is highly similar to Aβ in the homodimer. More importantly, in the heterodimer, the regions E3–H6, F19–E22, and I31–M35 of Aβ and the amyloid core region N20–T30 of hIAPP display higher β-sheet probability than they do in homodimer, implying their crucial roles in the formation of β-sheet-rich co-aggregates. Our study sheds light on the co-aggregation of Aβ and hIAPP at an atomic level, which will be helpful for an in-depth understanding of the molecular mechanism for epidemiological correlation of AD and T2D.