Modeling the Cu+ binding in the 1-16 region of the amyloid-β peptide involved in Alzheimer's disease.

The coordination of copper to the amyloid-β (1-16) (Aβ) peptide has been investigated because of its relevance for understanding Cu redox activity when the ion is embedded in peptides involved in neurodegenerative diseases. In this work, several reasonable models of Cu(+) coordination were built on the basis of experimental information and investigated by first-principles molecular dynamics simulations in the Car-Parrinello scheme. The propensity of a linear Nδ (His)-Cu-Nδ (His) coordination for Cu(+) is shown by all the models investigated here, with distortions due to weak interactions with the carbonyl O of His 6 and His 13 and with the amide N of His 14. Though the His 6-Cu-His 14 linear coordination is favored in truncated models, the His 13-Cu-His 14 linear coordination is favored by interactions present in the complete solvated and in vacuo models of Cu-Aβ (1-16). These interactions include steric hindrance for the expulsion of His 13, hydrogen bonds between Asp and His side chains and a network of electrostatic interactions stabilizing two separated 1-10 and 11-16 peptide regions. The role of linear His 13-Cu-His 14 coordination in stabilizing Cu(I) and in increasing the Cu(II)/Cu(I) reorganization energy can be therefore modulated by boundary conditions acting on the Aβ (1-16) ligand.