The role of metals in amyloid aggregation—Experiments and ab initio simulations

Abstract

AbstractWith a combination of modern spectroscopic techniques and numerical first principle simulations it is possible to investigate the physico‐chemical basis of the β‐amyloid aggregation phenomenon, which is suspected to be at the basis of the development of the Alzheimer disease. On the experimental side, in fact, X‐ray absorption spectroscopy can be successfully used to determine the atomic structure around the metal binding site in samples where β‐amyloid peptides are complexed with either Cu2+ or Zn2+ ions. Exploiting spectroscopic information obtained on a selected set of fragments of the natural Aβ‐peptide, the residues that along the sequence are coordinated to the metal are identified. Although copper data can be consistently interpreted assuming that oligopeptides encompassing the minimal 1–16 amino acidic sequence display a metal coordination mode which involves three Histidines (His6, His13, and His14), in complexes with zinc a four Histidines coordination mode is seen to be preferred. Lacking a fourth Histidine in the Aβ1–16 fragment, this geometrical arrangement hints to a Zn2+ promoted inter‐peptide aggregation mode. On the theoretical side, first principle ab initio molecular dynamics simulations of the Car–Parrinello type, which have proved to be of invaluable help in understanding the microscopic mechanisms of chemical bonding both in solid‐state physics and structural biophysics, have been employed in an effort to give a microscopic basis and find a phenomenological interpretation of the body of available experimental data on Aβ‐peptides–metal complexes. Using medium size PC‐clusters as well as larger parallel platforms, it is possible to deal with systems comprising 300–500 atoms and 1,000–2,000 electrons for simulation times as long as 2–3 ps. We present structural results that nicely compare with NMR and XAS data. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008