Computational studies on metal bound amyloid-beta peptide complexes: Implications for oligomerization

Amyloid-beta (Abeta) peptide is the primary component of the senile plaques that char-acterize Alzheimer's disease (AD). Numerous studies have shown that small soluble oligomers of Abeta have higher neurotoxicity than large, insoluble aggregates and fibrils. Brain tissue analysis has shown that excessive metal ions including zinc, copper and iron are co-localized with the plaques. In addition, in vitro studies suggest that these ions play an important role in the aggregation and toxicity of Abeta. Nevertheless, due to the large number of variables that must be controlled it is difficult to characterize the detailed mechanisms by which metal ions modulate Abeta aggregation. Although, some researchers have been able to identify several potential metal binding sites on Abeta using a variety of experimental techniques and conditions, there is no general agreement on the detailed coordination structures. Therefore, in this work, in silico methods have been utilized. To do this, quantum mechanics calculations were used to predict the most stable structures of metal-bound Abeta model complexes. Potential ligand exchange reactions and binding properties in terms of stability in various solvent conditions were also investigated in great detail. The parameters for different metal-residue coordination environments were generated to facilitate further studies of full metal-peptide complexes via molecular dynamics simulations. These simulations revealed changes in secondary structural from alpha-helices to beta-sheet in Abeta that were facilitated by metal coordination. Crucial beta-sheet sequences, salt bridges and hydrophobic inter-actions were identified. In general, the computational studies provide insight in to the details of metal-Abeta and Abeta-Abeta interactions during the initial steps of Abeta oligomerization.