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

Truncated and mutated amyloid-beta (A beta) peptides are models for systematic study-in homogeneous preparations-of the molecular origins of metal ion effects on A beta aggregation rates, types of aggregate structures formed, and cytotoxicity. The 3D geometry of bis-histidine imidazole coordination of Cu-II in fibrils of the nonapetide acetyl-A beta(13-21)H14A has been determined by powder N-14 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 the mutual orientation of the imidazole rings, for Cu-II in Ac-A beta(13-21)H14A fibrils are consistent with the proposed beta-sheet structural model and pairwise peptide interaction with Cu-II, with an alternating [-metal-vacancy-](n) pattern, along the N-terminal edge. Metal coordination does not significantly distort the intra-beta-strand peptide interactions, which provides a possible explanation for the acceleration of Ac-A beta(13-21)H14A fibrillization by Cu-II, through stabilization of the associated state and low-reorganization integration of beta-strand peptide pair precursors.