Abstract: Over the past two decades, stunning breakthroughs in the field of structural biology have continued to produce groundbreaking high-resolution structures of large, multi-component biomolecular machines. Comparative analyses of these static structures reveals the remarkable conformational flexibility of these machines and hints at the significant structural rearrangements that evidently accompany their functional cycles. Unfortunately, the experimental observation and characterization of these conformational dynamics is severely impeded by the size and complexity of biomolecular machines, severely limiting our understanding of the contributions that dynamics make to their functions. Using a combination of molecular genetic-, biochemical-, and single-molecule biophysical approaches, my research group aims to overcome these challenges and elucidate the precise roles that the conformational dynamics of biomolecular machines play in driving and controlling their functions. My seminar presentation will primarily focus on our studies of the mechanism and regulation of messenger RNA translation into protein by the ribosome, an essential step in gene expression. Specifically, I will discuss how thermally driven fluctuations of the ribosome and other essential translation components contribute to the mechanism and regulation of translation. Because the ribosome is the target of over half of all currently prescribed antibiotics and because of the growing list of human diseases to which deregulation of translation has been causally linked, our findings hold great promise for informing the development of next-generation antibiotics and small-molecule therapeutic agents that function by modulating the conformational dynamics of the translation machinery. Building on what we have learned from these studies, I will close my presentation by describing recent technological advances that are allowing us to investigate biomolecular dynamics which play important roles in gene expression and cellular physiology, but that have thus far remained difficult or impossible to investigate.