Grant: Operating Grant

The function of a protein derives from its three-dimensional structure and how it changes with time. Although very detailed pictures of protein molecules have been produced it is often the case that they do not completely explain results from functional biological assays, nor do they necessarily illuminate the path for protein engineering or rational drug design. This is, of course, not surprising. A three-dimensional static structure provides a description of the ground state of the molecule. Macromolecular function is, in many cases, highly dependent on excursions to excited molecular states that are only transiently formed and of very low population. Such molecular conformations have traditionally escaped detection using conventional methods for obtaining three-dimensional structural information. The goal of this research is to study how proteins fold into their three-dimensional structures by obtaining atomic level descriptions of the excited state intermediates that are formed along their folding pathways. Studies will also be performed to understand how proteins misfold into fibrilar structures that are implicated in a host of human diseases. Ultimately, an understanding of how such fibers are formed will lead to the rational design of pharmaceuticals that prevent their occurrence.