PtCl2(phen) disrupts the metal ions binding to amyloid-β peptide

Abstract

Platinum phenanthroline complexes have been found to inhibit Aβ aggregation and reduce Aβ caused neurotoxicity. Our previous results revealed the synergistic roles of phenanthroline ligand and Pt(ii) coordination in the inhibition of Aβ aggregation. In this work, the reactions of PtCl2(phen) with metal bound Aβ complexes were investigated. HPLC results show that the copper coordination decreases the reaction rate of PtCl2(phen) with Aβ1-16 and influences the distribution of products on HPLC profiles. EPR results reveal that Cu(2+) remains coordinated to the Aβ peptide upon the binding of [Pt(phen)](2+), however, the Cu(2+) coordination sites are changed. The formation of bimetallic coordination complex [Pt(phen)+Aβ1-16+Cu(II)] was confirmed by ESI-MS. Tandem MS analysis shows that, similar to the reaction of apo-Aβ peptide, the His6/His14 chelation is also the preferred binding mode for [Pt(phen)](2+) in the presence of copper ions. EPR spectra suggest that the binding of [Pt(phen)](2+) alters the copper coordination from mode I to mode II in Aβ. Tandem MS analysis indicates that His13 and N-terminal amine could be involved in the Cu(2+) coordination in the bimetallic adduct. Similar results were observed in the reaction of Zn(2+) bound Aβ peptide, although the different zinc binding residues were detected in the bimetallic complex. These results indicate that the binding of platinum complex disturbs the most favorable coordination sphere of Cu(2+)/Zn(2+) and turns these metal ions to the secondary coordination site on Aβ. The release of Cu(2+)/Zn(2+) occurs at low pH. This result suggests that the binding of [Pt(phen)](2+) scaffold could interfere with the binding of Zn(2+) and Cu(2+) to Aβ, thus reducing the metal-induced Aβ aggregation and toxicity.

Prediction of ligand effects in platinum-amyloid-β coordination

“…LFMM is a powerful modelling tool for the study of transition metal complexes and has previously found success in predicting their interactions with biomolecules. In this work, we apply the LFMM approach to a series of six Pt II complexes -as studied by Barnham 16,17,45 and others 19,20,21 -and their interaction with model fragments of the amyloid-β peptide in order to determine favourable metal binding modes as well as their influence on peptide secondary structure. Conformational space of Aβ was explored using δowεode εD with AεBER molecular mechanics parameters, followed by further optimisation using the semi-empirical PM7 method.…”

“…However, characterization of these Pt II (ligand)-Aβ complexes is difficult, with authors suggesting a variety of different metal binding modes 16,19,20 . Experimental evidence indicates that a series of platinated adducts are formed when Pt II (phenanthroline) complexes bind to Aβ, though the N-terminal His6 and His14 residues are the most common Pt II binding sites 16,19,20,21 .…”

Metal complexes of amino acids and peptides

“…The results are still contradictory but represent a significant contribution to the better understanding of these processes. 238 The Pt(II) induced rearrangement of Cu(II) coordination sites was reported in another study too, but the ROS production was not influenced. 210 The same technique was also applied to understand the effect of the metal ions on the misfolding and aggregation of the peptide.…”

Modeling of Platinum-Aryl Interaction with Amyloid-β Peptide

“…Firstly, the peptide fragment will be extended to at least the Aβ1-16 unit studied in experimental work 19,54 . This would allow confirmation of platinum binding modes on a more realistic model of biological Aβ.…”