Amyloid aggregation intermediates are metastable protein species linked to toxicity and disease pathology and are emerging as therapeutic targets. These oligomeric aggregates are ill-characterized and their low concentration, low stability, and high polydispersity pose complex analytical challenges. We here present the use of mass spectrometry (MS)-based approaches to capture and isolate specific protein aggregates, effectively performing gas-phase purification, prior to structural characterization. This allows for studies of individual oligomeric states separated in high resolution according to assembly state and conformation, which is unattainable using condensed-phase techniques. We describe how intact protein assemblies can be separated, manipulated, and spectroscopically analyzed in the gas phase and highlight how this has recently been used to gain unique structural insights into oligomeric aggregates.
