The possible mechanism of the competitive substitution effect between Zn^2＋ and Cu^2＋ in the interactions with Aβ was investigated for the first time by a molecular modeling method. The results show that Zn^2＋ fails to substitute the Cu^2＋ in the complex of [Cu-H13(Nπ)-Y10(OH)] with a quasi-helix conformation and thus is of no effect on the inhibition of Cu^2＋ on Aβ aggregation. However, in striking contrast to Zn^2＋, Cu^2＋effectively substitutes the Zn^2＋ in the complexes of [Zn-H14(Nτ)-V12(CO)] and [Zn-H13(Nτ)- E11(CO)] almost without disturbing the conformation of the complexes. In addition, Cu^2＋ may even substitute the Zn^2＋ which crosslinks two Aβ strands by the bridge of [H13(Nτ)-Zn-H14(Nτ)].

Key words: zinc(II), copper(II), amyloid β-peptide, competitive substitution, molecular modeling