Accelerated Molecular Dynamics to Explore the Binding of Transition Metals to Amyloid-β

We report the accelerated molecular dynamics (aMD) simulation of amyloid-β (Aβ) peptides of four different lengths (16, 28, 40, and 42 residues) and their complexes when bound to Cu(II), Fe(II), or Zn(II). 600 ns equilibrated trajectory data were analyzed for each structure from three independent 200 ns aMD simulations, generating 16 aMD trajectories. We show that the presence of a metal ion leads to reduced size and decreased mobility relative to the free peptide due to the anchoring effect of the ions. The reduced mobility was shown largely to be due to the restricted movement in N-terminal residues, most notably Asp1 and His6 that are involved in the metal-ion coordination in all cases. Significant disruption of the secondary structure and patterns of salt bridge interactions arise on the coordination of metal ions. In this regard, similarities were noted between results for Zn(II) and Fe(II), whereas results for Cu(II) are more comparable to that of the free peptides. Reweighting of free energy surfaces was carried out from aMD data to identify the properties and descriptions of local minima structures.