Copper(II)-bis-histidine coordination structure in a fibrillar amyloid ß-peptide fragment and model complexes revealed by electron spin echo envelope modulation spectroscopy.

Truncated and mutated amyloid-ß (Aß) peptides are models for systematic study-in homogeneous preparations-of the molecular origins of metal ion effects on Aß 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-Aß(13-21)H14A has been determined by powder (14) N 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-Aß(13-21)H14A fibrils are consistent with the proposed ß-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-ß-strand peptide interactions, which provides a possible explanation for the acceleration of Ac-Aß(13-21)H14A fibrillization by Cu(II) , through stabilization of the associated state and low-reorganization integration of ß-strand peptide pair precursors.

Local structure and global patterning of Cu2+ binding in fibrillar amyloid-ß [Aß(1-40)] protein.

The amyloid-ß (Aß) protein forms fibrils and higher-order plaque aggegrates in Alzheimer's disease (AD) brain. The copper ion, Cu(2+), is found at high concentrations in plaques, but its role in AD etiology is unclear. We use high-resolution pulsed electron paramagnetic resonance spectroscopy to characterize the coordination structure of Cu(2+) in the fibrillar form of full-length Aß(1-40). The results reveal a bis-cis-histidine (His) equatorial Cu(2+) coordination geometry and participation of all three N-terminal His residues in Cu(2+) binding. A model is proposed in which Cu(2+)-His6/His13 and Cu(2+)-His6/His14 sites alternate along the fibril axis on opposite sides of the ß-sheet fibril structure. The local intra-ß-strand coordination structure is not conducive to Cu(2+)/Cu(+) redox-linked coordination changes, and the global arrangement of Cu sites precludes facile multielectron and bridged-metal site reactivity. This indicates that the fibrillar form of Aß suppresses Cu redox cycling and reactive oxygen species production. The configuration suggests application of Cu(2+)-Aß fibrils as an amyloid architecture for switchable electron charge/spin coupling and redox reactivity.

The equilibrium intrinsic crystal-liquid interface of colloids.

We use confocal microscopy to study an equilibrated crystal-liquid interface in a colloidal suspension. Capillary waves roughen the surface, but locally the intrinsic interface is sharply defined. We use local measurements of the structure and dynamics to characterize the intrinsic interface, and different measurements find slightly different widths of this interface. In terms of the particle diameter d, this width is either 1.5d (based on structural information) or 2.4d (based on dynamics), both not much larger than the particle size. This work is the first direct experimental visualization of an equilibrated crystal-liquid interface.

OPTESIM, a versatile toolbox for numerical simulation of electron spin echo envelope modulation (ESEEM) that features hybrid optimization and statistical assessment of parameters.

Electron spin echo envelope modulation (ESEEM) is a technique of pulsed-electron paramagnetic resonance (EPR) spectroscopy. The analyis of ESEEM data to extract information about the nuclear and electronic structure of a disordered (powder) paramagnetic system requires accurate and efficient numerical simulations. A single coupled nucleus of known nuclear g value (g(N)) and spin I=1 can have up to eight adjustable parameters in the nuclear part of the spin Hamiltonian. We have developed OPTESIM, an ESEEM simulation toolbox, for automated numerical simulation of powder two- and three-pulse one-dimensional ESEEM for arbitrary number (N) and type (I, g(N)) of coupled nuclei, and arbitrary mutual orientations of the hyperfine tensor principal axis systems for N>1. OPTESIM is based in the Matlab environment, and includes the following features: (1) a fast algorithm for translation of the spin Hamiltonian into simulated ESEEM, (2) different optimization methods that can be hybridized to achieve an efficient coarse-to-fine grained search of the parameter space and convergence to a global minimum, (3) statistical analysis of the simulation parameters, which allows the identification of simultaneous confidence regions at specific confidence levels. OPTESIM also includes a geometry-preserving spherical averaging algorithm as default for N>1, and global optimization over multiple experimental conditions, such as the dephasing time (tau) for three-pulse ESEEM, and external magnetic field values. Application examples for simulation of (14)N coupling (N=1, N=2) in biological and chemical model paramagnets are included. Automated, optimized simulations by using OPTESIM lead to a convergence on dramatically shorter time scales, relative to manual simulations.