화학공학소재연구정보센터
Journal of Physical Chemistry B, Vol.125, No.8, 2050-2060, 2021
Mechanistic Insights into the Co-Aggregation of A beta 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, A beta and hIAPP, has been proposed as a potential molecular mechanism. However, the detailed A beta-hIAPP interactions and structural characteristics of co-aggregates are mostly unknown at atomic level. Here, we explore the conformational ensembles of the A beta-hIAPP heterodimer and A beta or hIAPP homodimer by performing all-atom explicit-solvent replica exchange molecular dynamic simulations. Our simulations show that the interaction propensity of A beta-hIAPP in the heterodimer is comparable with that of A beta-A beta/hIAPP-hIAPP in the homodimer. Similar hot spot residues of A beta/hIAPP in the homodimer and heterodimer are identified, indicating that both A beta and hIAPP have similar molecular recognition sites for self-aggregation and co-aggregation. A beta in the heterodimer possesses three high beta-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 A beta in the homodimer. More importantly, in the heterodimer, the regions E3-H6, F19-E22, and I31-M35 of A beta and the amyloid core region N20-T30 of hIAPP display higher A beta-sheet probability than they do in homodimer, implying their crucial roles in the formation of fisheet-rich co-aggregates. Our study sheds light on the co-aggregation of A beta 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.