Identification of [PtCl2(phen)] Binding Modes in Amyloid-β Peptide and the Mechanism of Aggregation Inhibition

Platinum phenanthroline complexes inhibit amyloid-beta (A beta) aggregation and reduce A beta-caused neurotoxicity [Proc. Natl. Acad. Sci., 2008, 105, 6813-6818]. In this study, we investigated the interactions of A beta(1-16) with [PtCl2(phen)] (phen=1,10-phenanthroline) using HPLC, ESI-MS, and NMR spectroscopy, and characterized the identity of products using tandem mass spectrometry. Results indicated that the phenanthroline ligand could induce noncovalent interactions between A beta peptide and platinum complexes, leading to rapid A beta platination. Multiple products were generated in the reaction, in which His6/His14 chelation was preferentially formed. Coordination of Asp7, His13, and Lys16 was also detected in other products. The majority of products were monoplatinated adducts with binding of the {Pt(phen)} scaffold, which impeded intermolecular interactions between A beta peptides. Moreover, noncovalent interactions were confirmed by the interaction between A beta peptide and [Pt(phen)(2)]Cl-2. The synergistic roles of the phen ligand and platinum(II) atom in the inhibition of A beta aggregation are discussed.