A precise network of interacting biomolecules, including proteins, DNA and lipids, allow for the function and control of all biological processes.  Consequently, to understand these processes and offer potential for intervention, for example in the treatment of human disease, it is useful to have an understanding of the molecular components and their binding interactions.  However, structural characterisation of such complex, heterogeneous and dynamic systems remains a challenge, in part due to analytical limitations of current structural biology approaches. This is particularly true in the context of protein misfolding diseases arising from the failure of a specific peptide or protein to adopt, or remain in, its native functional conformational state.  Despite extensive efforts to identify the mechanisms by which protein misfolding diseases result, the way in which natively soluble proteins misfold to produce toxic aggregates is not fully understood, and a lack of atomic level understanding has hampered rational design of therapeutics.

Ion-mobility mass-spectrometry (IM-MS) has emerged as a complementary tool for biomolecule structure determination, and in some cases a structural biology method in its own right.  It is capable of defining identity, stoichiometry, size, structural arrangement and subunit interactions in a biomolecular assembly in a single experiment. Here we will present examples, primarily focussed on the proteins alpha synuclein and amyloid beta (associated with Parkinson’s and Alzheimer’s disease respectively) where mass spectrometry has offered new insight into protein aggregation pathways.  We will also discuss the application of mass spectrometry to investigate the interaction of these proteins with small molecules and lipids.