Mass spectrometry at the frontiers of molecular medicine

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Many of our vital cellular processes are controlled and carried out by proteins that come together to form large and dynamic machineries. As cornerstones of the proper functioning of the cell, unsurprisingly many of these protein assemblies play important roles in human health. These range from ensuring that other proteins are correctly folded and assembled; to being responsible for clearing and degrading toxic species; and allowing the correct movement of molecules and ions in and around the cell. As such many of these protein machineries are important drug targets, with the binding of these small molecules acting to stimulate or reduce their activity, and hence mitigate disease states. Obtaining a complete inventory and description of these machineries, in both healthy and disease states, therefore represents one of the continuing grand challenges of biology. The difficulty in studying the structure of these molecules is that they are often very dynamic, that is their composition and shape can change, particularly when they interact with other molecules or are subject to external stresses. Infact the nature, scale and frequency of these fluctuations themselves play a vital part in governing function. Here we propose to develop and apply mass spectrometry for the study of both the structure and dynamics of protein assemblies, and will tackle two of the most notoriously difficult classes of biomolecules: the molecular chaperones, involved in protecting proteins from unwanted interactions; and membrane complexes that regulate the transport of small molecules into and out of the cell. Mass spectrometry represents a particularly attractive approach as it is remarkably general in its applicability, and has a high resolution of separation in both space and time: in other words it is well suited to looking at mixtures of proteins, and to monitor the transitions they undergo. The output of this research will lead us towards a complete understanding of the sizes, shapes and movements of these cellular machineries, as well as a means for evaluating the effects of small molecules as potential therapeutic strategies.