Cu(II) coordination structure determinants of the fibrillization switch in Abeta peptides

Alzheimer's Disease (AD) is associated with the aggregation and fibrillization of the beta-amyloid protein (Abeta). The coordination of Cu(II) by peptide histidine imidazole sidechains is proposed to play an important role in determining the fibrillization ``switch'' [$1$]. We have developed techniques of powder X-band electron spin echo envelope modulation (ESEEM) spectroscopy to determine the 3D molecular structure of the Cu(II)-histidine imidazole coordination in cryotrapped soluble and fibrillar forms of Abeta peptides, in order to gain insight into the factors that govern fibrillization. We use hybrid optimization-based OPTESIM [$2$] simulation of the double quantum harmonic feature to determine the mutual orientation of the imidazole rings in Cu(II)--bis-imidazole complexes and in Abeta(13-21) peptides. The Cu(II) coordination mode and assembly constraints in fibrils are revealed. [1] Dong , J., et al., \textit{Proc. Natl. Acad. Sci.,} 2007, $104$, 13313. [2] Sun, L., et al., \textit{J. Magn. Reson.} 2009, \underline {\textit{200}}, 21.