Combined Mass Spectrometric and Optical Spectroscopic Investigation of Biological Molecules in Controlled Micro-environments

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The development and application of new tools and techniques to identify molecules and study their properties can be transformative, with long-term impact on fields ranging from chemistry and physics to medicine and biology. The development of such tools is the aim of research in the Jockusch laboratory. In particular, we focus on the development of new techniques that extend the uses of mass spectrometry (MS) in order to enhance the understanding of how biological molecules such as proteins are affected by their environment. This is important because proteins play a central role in biology. For example, proteins that are ‘misfolded’ have negative impacts on health, and are associated with many devastating diseases including Alzheimer’s and Parkinson’s diseases. However, proteins and other biomolecules do not generally act in isolation; their behavior is modulated by a complex web of molecular interactions. In order to dissect the complexity present in Nature, it is valuable to study simplified systems whose complexity can gradually be built up in a carefully controlled fashion. Thus, the Jockusch laboratory’s approach to understanding the properties of biomolecules is to study them in a highly-controlled environment: isolated inside a mass spectrometer. This enables the separation of intrinsic molecular properties from effects of the molecular environment. In subsequent investigations, pieces of the molecular environment such as water molecules, metal ion, or other binding partners will be added to form complexes and clusters, thus enabling discovery of how additional specific interactions modulate or control the molecular properties of interest. The Jockusch laboratory has added a new dimension of information to tandem mass spectrometry analysis by interfacing MS with a flexible interface for gas-phase laser spectroscopic experiments. In particular, we are spearheading the use of fluorescence and fluorescence resonance energy transfer (FRET) techniques to probe conformation and other functional characteristics of gaseous biomolecular ions and their complexes. FRET is an example of a transformative technique, developed by physicists and subsequently adopted by biologists for the study of protein conformation and dynamics. Its use enabled the study of even single molecules in solution – an amazing advance from ensemble techniques commonly used. The development of gas-phase FRET promises to be equally transformative. Only two other laboratories world-wide have capabilities and expertise similar to the Jockusch lab (at Harvard, and ETH Zurich), having implemented the powerful combination of mass spectrometry and fluorescence techniques. Not only will the techniques and tools developed in the Jockusch lab push the boundaries of MS-enabled science, this cutting-edge research program provides an excellent training environment for the next generation of Canadian Scientists.