Grant: Discovery Grants Program - Individual

Proteins are the moving parts' of the molecular machinery of cells. They carry out a range of highly specialized tasks, such as catalyzing biochemical reactions and transducing signals. Yet neither structures of individual proteins nor protein complexes can be reliably predicted today our knowledge of the physics of protein folding and interaction remains incomplete. A key factor hampering progress is the large computational cost of traditional molecular dynamics simulations, leaving many problems out of reach to computation. Adding urgency to this problem is the increased emphasis of current biophysical experiments on large and complex conformational transitions, including between ordered and disordered states, as a way to understand how proteins carry out their functions. One component of my research program over the next five years is the development of a systematic procedure for formulating coarse-grained potential energy functions in molecular simulations. I will apply it to further enhance a unique intermediate-resolution model for protein folding and interaction that was recently developed in my group and that hits a sweet-spot' in the tradeoff between detail and computational speed. With this coarse-grained model, I will investigate the biophysical basis of protein conformational switching in two complementary areas. (A) We will investigate the factors that allow metamorphic' proteins to abruptly and reversibly switch between entirely different three-dimensional shapes, triggered by a binding event or as in evolutionary processes by mutations. A hypothesis that I will explore is whether these shape-shifting proteins represent evolutionary bridges' to new protein shapes. In the second area, (B) we will study how conformational transitions in disordered proteins, which lack a stable three-dimensional shape, form the molecular basis for the functional behavior of this type of flexible proteins, including molecular recognition. This research program will provide much needed new techniques for systematic coarse-graining in molecular simulations. Equally important, it will provide a deeper understanding of the physics of conformational switching in proteins and thereby enhance our understanding of the cellular machinery. The program will also benefit the biotechnology industry by laying the foundation for the development of biosensors or targeted drug-delivery systems based on conformational switching. **