Copper(II)-bis-Histidine Coordination Structure in Fibrillar Amyloid-β Peptide Fragment and Model Complexes Revealed by using Electron Spin Echo Envelope Modulation Spectroscopy

摘要

Truncated and mutated amyloid-β (Aβ) peptides are models for systematic study of the molecular origins of metal ion effects on Aβ aggregation rates, types of aggregate structures formed, and cytotoxicity, in homogeneous preparations. The 3-D geometry of bis-histidine imidazole coordination of Cu(II) in fibrils of the nonapetide, acetyl-Aβ(13-21)H14A, is determined by using powder ¹⁴N electron spin echo envelope modulation (ESEEM) spectroscopy. The method of simulation of the anisotropic combination modulation is described, and benchmarked for a Cu(II)-bis-cis-imidazole complex of known structure. The revealed bis-cis coordination mode, and mutual orientation of the imidazole rings, for Cu(II) in Ac-Aβ(13-21)H14A fibrils are consistent with the proposed β-sheet structural model, and pair-wise peptide interaction with Cu(II), with alternating [–metal–vacancy–]n pattern, along the N-terminal edge. Metal coordination does not significantly distort the intra-β-strand peptide interactions, which provides a rationale for the Cu(II)-acceleration of Ac-Aβ(13-21)H14A fibrillization, through stabilization of the associated state, and low-reorganization integration of β-strand peptide pair precursors.