|Research Area||Bio Sciences|
|Principal Investigator(s)||Paolo Giannozzi|
The interest in elucidating the role of metals in the development of amyloid diseases (to the group of which the Alzheimer’s disease belongs) has significantly increased after noticing that Cu and Zn chelators can be used to solubilize the amyloid-beta aggregates (Aβ-aggregates) which appear to make up the fibrillar material associated with AD.
There exist in the literature somewhat conflicting statements on whether Cu2+ and Zn2+ ions can provide protection against or act as promoters of plaques formation. Recent X-ray Absorption Spectroscopy experiments designed to study the metal atomic environment in Cu-Aβ and Zn-Aβ complexes have been able to detect visible differences between Zn and Cu coordination modes.
Even on the specific geometrical structure of the Cu binding site experimental data are not fully conclusive. On the one hand, in fact, NMR data on copper complexed with Aβ1-28 and Aβ1-40 peptides suggest that three Histidines (His6, His13 and His14) are coordinated to the metal with the fourth ligand being the N-terminal nitrogen. On the other, XAS experiments on various portions of the natural Aβ protein and NMR/EPR experiments on the Aβ1-16 and Aβ1-28 peptides, all point to the conclusion that, besides the above three Histidines, the fourth copper ligand is most probably the oxygen of Tyr10. Clarifying this question is not without interest, because it is expected that the more or less open structure of the peptide can strongly influence its aggregation propensity. Typically one may suspect that a coordination mode where the N-terminal is not bound to Cu will give rise to a more open geometry and thus probably more prone to aggregation structure.
For the purpose of elucidating the structure of the (Cu2+/Zn2+)-Aβ binding site, simulations of the Car-Parrinello type appear to be the most appropriate tool, as they provide a first principle quantum mechanical computation of the atomic force field. In this project we propose to carry out a thorough first principle study of the metal environment in Cu-Aβ and Zn-Aβ complexes.