Computational Study of Amyloidβ42 Familial Mutations and Metal Interaction: Impact on Monomers and Aggregates Dynamical Behaviors: Impact on Monomers and Aggregates Dynamical Behaviors

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 Aβ 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 Aβ aggregation patterns observed in familial mutations. The amyloid-β aggregation process is still widely unknown and difficult to experimentally determine. This work uses a multiscale computational protocol to study possible interfering factors on the aggregation process. The focus is placed on the effect of Cu and Al metal ions, together with four well-known familial mutations (E22Q, E22G, E22K, and D23N), on the monomeric and fibrillar species.