Scientists have used mass spectrometry for more than a century to separate and detect gaseous ions - from the historic applications to separate the isotopes of neon through to elucidating the structure of natural products. With the advent of electrospray came the ability to study intact proteins and subsequently proteins in their folded states with non-covalent interactions preserved.
Our first examples of molecular chaperones in complex with folded ligands highlighted opportunities for us to probe the heterogeneity within complexes as they form and dissociate along reaction pathways. Using these experiments we deduced equilibrium constants and, when combined with proteomics, studied the influence of post-translational modifications on cellular reaction pathways.
Recent breakthroughs allow mass spectrometry to be applied to membrane protein complexes and allow us to probe small molecule binding to multiprotein targets.
For membrane proteins assemblies, released directly into the gas phase of the mass spectrometer from micelles or lipid-based solubilisation vehicles, we are able to capture small molecule binding. I will illustrate these capabilities with a range of receptors and transporters including G-protein coupled receptors and ABC transporters.
In my lecture I will also demonstrate how we can exploit new mass spectrometry approaches to understand protein interactions from lipidic environments. These experiments are allowing us to focus on the numerous roles played by lipids in governing interactions and in stabilising different conformations of membrane proteins. Understanding the interplay between lipids, proteins and drugs is not only a fascinating line of research but will, I believe, provide vital information for next generation therapeutics.