Introduction of d-Glutamate at a Critical Residue of Aβ42 Stabilizes a Prefibrillary Aggregate with Enhanced Toxicity.

The amyloid beta peptide 42 (Aβ42) is an aggregation-prone peptide that plays a pivotal role in Alzheimer's disease. We report that a subtle perturbation to the peptide through a single chirality change at glutamate 22 leads to a pronounced delay in the β-sheet adoption of the peptide. This was accompanied by an attenuated propensity of the peptide to form fibrils, which was correlated with changes at the level of the fibrillary architecture. Strikingly, the incorporation of d-glutamate was found to stabilize a soluble, ordered macromolecular assembly with enhanced cytotoxicity to PC12 cells, highlighting the importance of advanced prefibrillary Aβ aggregates in neurotoxicity

Asymmetric catalysis with 7-ring chelate diphosphines: DIOP, BINAP and conformational mobility

The conformations of two classes of 7-ring diphosphine metal chelate have been analysed, based on DIOP- or BINAP-type structures. A combination of X-ray analysis, DFT calculations, data analysis based on the CDS structure database and solution NMR studies has been employed. The conformational flexibility of DIOP-type structures has been endorsed, and the scope of BINAP complex flexibility defined. BINAP complexes possess an intrinsic conformational mobility. Analysis of the metal-adjacent torsion angles C-P-M-P′ and C′-P′-M-P provides a useful probe for the ligand-metal environment, and may be more generally useful. © 2010 Elsevier Ltd. All rights reserved

Chiral recognition in contact ion-pairs; observation, characterization and analysis

Chiral ion-pairs are playing an increasingly important role in asymmetric catalysis. In order to understand the source of molecular recognition, a simple model system based on a BINAP-Rh(dialkene) cation and a BINOL borate anion was studied for both diastereomeric forms. It was discovered that one of these was energetically preferred and methods for quantifying the difference were devised using 31P NMR. The effect was general over a series of bis-binaphthyl borate anions, and required cycloocta-1,5-diene rather than bicyclohepta[2.2.1]diene as the dialkene component. The 1H NMR spectra of the cation in the parent ion pairs showed a range of anion-induced chemical shifts, their specificity implying selectivity in the ion-pair contact. X-ray structures of the two cyclooctadiene complexes were obtained and it proved possible to analyse the preferred contacts of individual ion-pairs. Rather than involving specific π-π, CH-π and CH-O intermolecular forces, the preference for one diastereomer in the COD case is based on dispersion forces that respond to the ability to pack the dialkene, and particularly its sp3 units, for maximum interaction with a concave naphthyl fragment. This interpretation is supported by analysis of one related NBD complex. © 2013 The Royal Society of Chemistry

A Tailored HPLC Purification Protocol That Yields High-purity Amyloid Beta 42 and Amyloid Beta 40 Peptides, Capable of Oligomer Formation.

Amyloidogenic peptides such as the Alzheimer's disease-implicated Amyloid beta (Aβ), can present a significant challenge when trying to obtain high purity material. Here we present a tailored HPLC purification protocol to produce high-purity amyloid beta 42 (Aβ42) and amyloid beta 40 (Aβ40) peptides. We have found that the combination of commercially available hydrophobic poly(styrene/divinylbenzene) stationary phase, polymer laboratory reverse phase - styrenedivinylbenzene (PLRP-S) under high pH conditions, enables the attainment of high purity (>95%) Aβ42 in a single chromatographic run. The purification is highly reproducible and can be amended to both semi-preparative and analytical conditions depending upon the amount of material wished to be purified. The protocol can also be applied to the Aβ40 peptide with identical success and without the need to alter the method