Structural insights into the interaction of platinum-based inhibitors with the Alzheimer's disease amyloid-β peptide

Abstract

Extended X-ray absorption fine structure spectroscopy, mass spectrometry, dynamic light scattering and density functional theory are combined to derive structural models for the interaction of neurotoxicity-ablating platinum-based compounds with the amyloid-β peptide.

Prediction of ligand effects in platinum-amyloid-β coordination

“…However, comparison with the geometrical data for the low energy conformations (Table 5) clearly shows that these stable structures are not significantly different from the average conformation in each case, suggesting that the platinum geometry is not especially important in determining complex stability. It is also notable that these Pt-N distances are in good agreement with those of Streltsov et al 22…”

“…Computational approaches may provide clear insight into this problem, without the need for complex synthesis. Of particular note is work by Streltsov et al, which combined Extended Xray Absorption Fine Structure (EXAFS) and Density Functional Theory (DFT) data for a series of model Pt II complexes to provide predictions of metal-aβ binding modes 22 .…”

Ruthenium(II) polypyridyl complexes with hydrophobic ancillary ligand as Aβ aggregation inhibitors

“…Ligand txbg shows interactions with N-terminal amino acids (residues 8 to 16) like other phenanthrolines. Enhanced potential of LPtCl 2 complexes is proposed to be a result of fundamental role of phenanthroline played in directing the metal complex to appropriate Aβ site and further stabilizing the binding via π-π interactions [12,24]. In case of complex 2, unlike N-terminal binding of txbg, interactions involve non-covalent binding of metal complex to central hydrophobic cluster of Aβ (residues 17-21) and C-terminal of Aβ.…”

“…Further phenanthroline interacts with aromatic residues of Aβ by π-π interactions. For the cis-platin, a completely different mode of binding takes place which involves covalent binding of Pt(II) with sulphur of Met residue of Aβ [12,13,24]. Although the adducts are formed by platination of Aβ, cis-platin exhibits no potential against Aβ aggregation indicating the crucial role of non-covalent π-π interaction in L-PtCl 2 Aβ binding.…”

Metal complexes of amino acids and peptides

“…210 The same technique was also applied to understand the effect of the metal ions on the misfolding and aggregation of the peptide. 240 Aluminium(III) compounds are also often considered to be responsible for the development of AD. 211 It was also demonstrated using fluorescence spectroscopy that Cu(II) binding affinity of Ab is almost two orders of magnitude weaker at pH 5.0 than at pH 7.3 and this was explained by the protonation of His residues.…”