Membrane proteins currently represent 60 % of all protein therapeutic targets. Membrane proteins are analytically challenging to study given their insolubility in water, requiring the use of technologies such as detergent micelles or nanodiscs to retain their native structure upon removal from the lipid membrane. Recently native mass spectrometry (MS) has proven itself as a tool readily capable of studying these detergent solubilized species. MS analysis of membrane proteins requires careful optimization of instrumental parameters employed in order to preserve a native like structure for the proteins within the gas phase, while simultaneously handling detergent related noise. The addition of ion mobility separations to native MS of membrane proteins not only aids in management of detergent noise, but also allows for gas-phase structural studies of membrane protein-ligand systems. Current aims for these studies include probing regiospecifity of ligand binding, as well as identification of an endogenous ligand, of pharmaceutically relevant 18kDa Translocator Protein (TSPO).
Membrane interacting peptides can also be studied via IM-MS. Amylogenic peptides, such as islet amyloid polypeptide (IAPP), are thought to be associated to disease states by causing dyshomeostasis in cells upon insertion into biological membranes. These peptides can be inserted into nanodiscs, which mimic membranes, and form different aggregate species. Using IM-MS derived lipid-peptide stoichiometries and collisional cross section measurements of these species, along with computational methods, we aim to determine the insertion and membrane disruption mechanisms of amylogenic peptides.