Different zinc(II) complex species and binding modes at Aβ N-terminus drive distinct long range cross-talks in the Aβ monomers

The present study addresses the reconstruction of the free-energy landscapes of amyloid-beta1-42 (Aβ42) coordinated respectively with one and two zinc ions, to scrutinize whether different Aβ-zinc complex species, i.e., mononuclear and dinuclear metal complexes, induce different Aβ conformation features. We found a subtle switch of intramolecular interactions, depending both on the zinc coordination environment and on the peptide to zinc stoichiometric ratio. On the one side, hairpin-like structures are predominant in mononuclear complexes, where a salt-bridge that involves Lys28-Glu22 and Lys16-Asp23 is stabilized. On the other side, elongated conformations are instead stabilized in the dinuclear zinc complexes. Experimental studies of atomic force microscopy as well as of zinc-Aβ complex species distribution diagrams provide evidence that the theoretical calculations can be rationalized in terms of the correlation between the increased amount of amorphous aggregates and the Aβ/Zn2+ ratio.