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ESI-IMS–MS: A method for rapid analysis of protein aggregation and its inhibition by small molecules

Young, Lydia M., Saunders, Janet C., Mahood, Rachel A., Revill, Charlotte H., Foster, Richard J., Ashcroft, Alison E., Radford, Sheena E.
Methods 2016 v.95 pp. 62-69
amyloid, ligands, rapid methods, spectroscopy, therapeutics
Electrospray ionisation-ion mobility spectrometry–mass spectrometry (ESI-IMS–MS) is a powerful method for the study of conformational changes in protein complexes, including oligomeric species populated during protein self-aggregation into amyloid fibrils. Information on the mass, stability, cross-sectional area and ligand binding capability of each transiently populated intermediate, present in the heterogeneous mixture of assembling species, can be determined individually in a single experiment in real-time. Determining the structural characterisation of oligomeric species and alterations in self-assembly pathways observed in the presence of small molecule inhibitors is of great importance, given the urgent demand for effective therapeutics. Recent studies have demonstrated the capability of ESI-IMS–MS to identify small molecule modulators of amyloid assembly and to determine the mechanism by which they interact (positive, negative, non-specific binding, or colloidal) in a high-throughput format. Here, we demonstrate these advances using self-assembly of Aβ40 as an example, and reveal two new inhibitors of Aβ40 fibrillation.