Fe2+ binding on amyloid -peptide promotes aggregation

The metal ions Zn2+, Cu2+, and Fe2+ play a significant role in the aggregation mechanism of A peptides. However, the nature of binding between metal and peptide has remained elusive; the detailed information on this from the experimental study is very difficult. Density functional theory (dft) (M06-2X/6-311++G (2df,2pd) +LANL2DZ) has employed to determine the force field resulting due to metal and histidine interaction. We performed 200 ns molecular dynamics (MD) simulation on A(1-42)-Zn2+, A(1-42)-Cu2+, and A(1-42)-Fe2+ systems in explicit water with different combination of coordinating residues including the three Histidine residues in the N-terminal. The present investigation, the A(1-42)-Zn2+ system possess three turn conformations separated by coil structure. Zn2+ binding caused the loss of the helical structure of N-terminal residues which transformed into the S-shaped conformation. Zn2+ has reduced the coil and increases the turn content of the peptide compared with experimental study. On the other hand, the Cu2+ binds with peptide, sheet formation is observed at the N-terminal residues of the peptide. Fe2+ binding is to promote the formation of Glu22-Lys28 salt-bridge which stabilized the turn conformation in the Phe19-Gly25 residues, subsequently sheets were observed at His13-Lys18 and Gly29-Gly37 residues. The turn conformation facilitates the sheets are arranged in parallel by enhancing the hydrophobic contact between Gly25 and Met35, Lys16 and Met35, Leu17 and Leu34, Val18 and Leu34 residues. The Fe2+ binding reduced the helix structure and increases the sheet content in the peptide, which suggested, Fe2+ promotes the oligomerization by enhancing the peptide-peptide interaction. Proteins 2016; 84:1257-1274. (c) 2016 Wiley Periodicals, Inc.