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

With a combination of modern spectroscopic techniques and numerical first principle simulations it is possible to investigate the physico-chemical basis of the P-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 P-amyloid peptides are complexed with either Cu2+ or Zn2+ ions. Exploiting spectroscopic information obtained on a selected set of fragments of the natural A beta-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 (HiS(6), HiS(13), and His(14)), in complexes with zinc a four Histidines coordination mode is seen to be preferred. Lacking a fourth Histidine in the A beta(1-16) 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 A beta-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. (c) 2008 Wiley Periodicals, Inc.