Zinc binding promotes greater hydrophobicity in Alzheimer's Aβ42 peptide than copper binding: Molecular dynamics and solvation thermodynamics studies.

The aggregation of Aβ42 peptides is considered as one of the main causes for the development of Alzheimer's disease. In this context, Zn2+ and Cu2+ play a significant role in regulating the aggregation mechanism, due to changes in the structural and the solvation free energy of Aβ42. In practice, experimental studies are not able to determine the latter properties, since the Aβ42-Zn2+ and Aβ42-Cu2+ peptide complexes are intrinsically disordered, exhibiting rapid conformational changes in the aqueous environment. Here, we investigate atomic structural variations and the solvation thermodynamics of Aβ42, Aβ42-Cu2+ , and Aβ42-Zn2+ systems in explicit solvent (water) by using quantum chemical structures as templates for a metal binding site and combining extensive all-atom molecular dynamics (MD) simulations with a thorough solvation thermodynamic analysis. Our results show that the zinc and copper coordination results in a significant decrease of the solvation free energy in the C-terminal region (Met35-Val40), which in turn leads to a higher structural disorder. In contrast, the β-sheet formation at the same C-terminal region indicates a higher solvation free energy in the case of Aβ42. The solvation free energy of Aβ42 increases upon Zn2+ binding, due to the higher tendency of forming the β-sheet structure at the Leu17-Ala42 residues, in contrast to the case of binding with Cu2+ . Finally, we find the hydrophobicity of Aβ42-Zn2+ in water is greater than in the case of Aβ42-Cu2+ .