Conformational Disorder in Protein Function and Pathogenesis

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EXECUTIVE SUMMARY: The overarching objective of my research program is to uncover the molecular mechanisms that drive biological activity - and sometimes pathology - in proteins. My group's approach employs unique technologies developed in-house that allow us to monitor 'active' proteins directly as they mediate the processes that define life at the molecular level. The current proposal builds on our prior successes, enabling a deeper exploration of: ***(i) Conformational dynamics in enzyme catalysis ***(ii) Function and pathology in intrinsically disordered proteins***(iii) The structural and dynamic basis of activity modulation in proteins***(iv) Hydrogen / deuterium exchange for quantitative measurements of protein interactions ******BACKGROUND: The classical tools of structural biology (i.e., X-ray crystallography and classical structural NMR) provide exquisitely detailed 'snapshots' of the 'native structure' of proteins. However, if all proteins were actually as static as they appear in these 'snapshots', most would be completely non-functional. To achieve biological activity, proteins must access specific, higher energy conformations within an ensemble of 'native-like' structures that are populated via thermally-driven fluctuations known as 'conformational dynamics'. My group has developed a unique set of mass spectrometry-based tools that provide a detailed picture of conformational dynamics, and the conformational shifts that underlie virtually all biological processes. From this foundation, we explore the molecular processes that drive catalysis, complexation, protein folding and activity modulation in proteins.******IMPACT: The proposed research addresses fundamental questions that are of great significance to our understanding of protein function and pathogenesis at the molecular level. It is ambitious, but builds directly upon the foundation laid out in my previous two discovery periods, where my group has had substantial impact as measured by conventional academic standards (53 publications in high impact journals, over 70 invited talks etc.). Our technologies have been replicated by groups in Canada, the US, China, Isreal, New Zealand, Sweden and the UK. We have also had an unusually high degree of success at translating fundamental discoveries to practical applications in collaboration with numerous industrial partners. It is because of this success that our broader research program now includes distinct but heavily intertwined branches for discovery and knowledge translation / mobilization. These branches exhibit positive feedback, allowing us now to implement a discovery research program where our fundamental explorations of molecular mechanisms have a tangible impact on 'real world' applications, Canadian business trajectories and, ultimately, greatly enhanced training and career opportunities for HQP.*****