posted on 2024-02-26, 23:43authored byLorena Roldán-Martín, Mariona Sodupe, Jean-Didier Maréchal
One of the main hallmarks of Alzheimer’s Disease
is the
formation of β-amyloid plaques, whose formation may be enhanced
by metal binding or the appearance of familial mutations. In the present
study, the simultaneous effect of familial mutations (E22Q, E22G,
E22K, and D23N) and binding to metal ions (Cu(II) or Al(III)) is studied
at the Aβ42 monomeric and fibrillar levels. With
the application of GaMD and MD simulations, it is observed that the
effects of metal binding and mutations differ in the monomeric and
fibrillar forms. In the monomeric structures, without metal binding,
all mutations reduce the amount of α-helix and increase, in
some cases, the β-sheet content. In the presence of Cu(II) and
Al(III) metal ions, the peptide becomes less flexible, and the β-sheet
content decreases in favor of forming α-helix motifs that stabilize
the system through interhelical contacts. Regarding the fibrillar
structures, mutations decrease the opening of the fiber in the vertical
axis, thereby stabilizing the S-shaped structure of the fiber. This
effect is, in general, enhanced upon metal binding. These results
may explain the different Aβ42 aggregation patterns
observed in familial mutations.