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

• Published in: Chemistry : a European journal Vol. 17; no. 41; pp. 11657 - 11666
• Main Authors: Ma, Guolin, Huang, Fan, Pu, Xuewei, Jia, Liangyuan, Jiang, Tao, Li, Lianzhi, Liu, Yangzhong
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 04.10.2011; WILEY‐VCH Verlag
• Subjects: Alzheimer Disease - metabolism; Amino Acid Sequence; Amyloid beta-Peptides - chemistry; Binding Sites; Chromatography, High Pressure Liquid; Copper - chemistry; Ligands; Magnetic Resonance Spectroscopy; mass spectrometry; Models, Molecular; Organoplatinum Compounds - chemistry; peptides; Phenanthrolines - chemistry; platinum; Platinum - chemistry; Protein Binding; Protein Structure, Secondary; reaction mechanisms; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201101859

Platinum phenanthroline complexes inhibit amyloid‐β (Aβ) aggregation and reduce Aβ‐caused neurotoxicity [Proc. Natl. Acad. Sci., 2008, 105, 6813–6818]. In this study, we investigated the interactions of Aβ1–16 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 Aβ peptide and platinum complexes, leading to rapid Aβ 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 Aβ peptides. Moreover, noncovalent interactions were confirmed by the interaction between Aβ peptide and [Pt(phen)2]Cl2. The synergistic roles of the phen ligand and platinum(II) atom in the inhibition of Aβ aggregation are discussed. Crowd control: [PtCl2(phen)] (phen=1,10‐phenanthroline) has a dual role in the inhibition of amyloid‐β (Aβ) aggregation. The phen ligand induces noncovalent interactions between the Aβ peptide and platinum complexes, leading to rapid Aβ platination (see scheme). While multiple products were formed in the reaction, His6/His14 chelation is the most favorable [PtCl2(phen)] binding mode.