Development of integrative approaches to biomolecular structure determination

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The aim of this Discovery research program is to develop new ways to determine the structure of biomolecules by combining emerging experimental techniques with tools from physical chemistry, namely statistical mechanics and molecular simulation.  Proteins are life's little machines. These tiny molecules are responsible for replicating our DNA, turning food into energy, contracting our muscles, and conducting electrical signals in our nervous systems-among many other activities. The function of each protein depends on its structure: the specific three-dimensional shape that each protein folds into. We now know over 100,000 different protein structures, which are curated in the Protein Data Bank. These structures have helped to reveal the extraordinary story of how life functions at the molecular level. This story, however, is incomplete because there are many proteins and protein complexes (groups of proteins that stick together and form larger structures) that we still do not know. This is because not all proteins or complexes are amenable to the experimental techniques that structural biologists routinely use. This research program is focused on developing new ways to determine protein structures that combine experiments with sophisticated computational tools built upon the foundation of statistical mechanics. Our focus is on a range of emerging experimental techniques that produce sparse, ambiguous, or noisy data. There are many experiments that fall into this category, some of which have been around for decades. These experiments have not been widely used in structural biology in the past because the data they produce is difficult to interpret. My lab is working to combine these experiments with sophisticated computational tools that can overcome the challenges in interpretation, which will unlock new avenues for the determination of protein structure. Over the five year span of this Discovery Grant, my laboratory's objectives are to further develop combinations of experiment and computation that can solve current challenges in structural biology. My lab aims to establish proofs-of-principal that demonstrate the success and effectiveness of these methods on a variety of model systems. The long-term goal of this project is to enable a range of new approaches to structural biology that will allow us to reveal protein structures that are currently hidden. By providing structural biologists with new tools, we will contribute to a better understanding of how life functions at the molecular level.