Grant: Foundation Grant

Protein molecules play critical roles in cellular function and they catalyze many of the biochemical reactions that are necessary for life. The three-dimensional shapes of these molecules are necessary for guiding proper function and they can change with time due to interactions with other molecules, during the process of carrying out specific functions, or simply the result of random fluctuations. Although very detailed static pictures of protein molecules have been produced using traditional biophysical tools, macromolecular function and misfunction is, in many cases, intimately coupled to flexibility; knowledge of molecular motions therefore becomes critical. Thus, static pictures of proteins that have been generated to date often do not completely explain results from functional biological assays, nor do they necessarily illuminate the path for engineering new functions or for rational drug design. The goal of this research is to develop new Nuclear Magnetic Resonance (NMR) Spectroscopy based techniques for studying motional processes in proteins and for relating these to function and to apply the methodology to important protein systems that are implicated in cancer, neurodegeneration and amyloidosis. The insights obtained will augment the structure-function paradigm that has dominated our understanding of how proteins work to include the important role of molecular dynamics. They will inform how function can be manipulated by changing how parts of proteins move in relation to each other and provide clues about how to design, in a rational manner, new classes of drug molecules. Advances that are made in the laboratory will be translated into potential drugs through collaborations with leading medicinal chemists and clinician scientists.