Impact of Cu(II) Binding on Structures and Dynamics of Aβ42 Monomer and Dimer: Molecular Dynamics Study

The classical force field, which is compatible with the Amber force field 99SB, has been obtained for the interaction of Cu­(II) with monomer and dimers of amyloid-β peptides using the coordination where Cu­(II) is bound to His6, His13 (or His14), and Asp1 with distorted planar geometry. The newly developed force field and molecular dynamics simulation were employed to study the impact of Cu­(II) binding on structures and dynamics of Aβ42 monomer and dimers. It was shown that in the presence of Cu­(II) the β content of monomer is reduced substantially compared with the wild-type Aβ42 suggesting that, in accord with experiments, metal ions facilitate formation of amorphous aggregates rather than amyloid fibrils with cross-β structures. In addition, one possible mechanism for amorphous assembly is that the Asp23–Lys28 salt bridge, which plays a crucial role in β sheet formation, becomes more flexible upon copper ion binding to the Aβ N-terminus. The simulation of dimers was conducted with the Cu­(II)/Aβ stoichiometric ratios of 1:1 and 1:2. For the 1:1 ratio Cu­(II) delays the Aβ dimerization process as observed in a number of experiments. The mechanism underlying this phenomenon is associated with slow formation of interchain salt bridges in dimer as well as with decreased hydrophobicity of monomer upon Cu-binding.