Multiscale structural dynamics of membrane protein complexes

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Multiscale structural dynamics of membrane protein complexes Proteins are constantly in motion, and these dynamics are critical for proper protein folding and cellular function. However, it is not entirely clear how real-time protein dynamics influence folding or regulate conformational changes. Recently, I have shown that dynamic changes during folding of a bacterial multidrug efflux pump can lead to erroneous protein topology and potentially compromise the capacity of bacteria to develop drug resistance. Efflux pumps, aside from contributing to drug resistance and associated health problems, also play fundamental roles in bacteria exporting various toxins, communicating with other bacteria, and helping to shape the surrounding ecosystem. I have shown that dynamic changes in protein structure start very early, while proteins are still being synthesized on the ribosome. These dynamics play critical roles as a new protein is modified, folded, targeted, and inserted into the membrane, but dynamics persist in fully mature proteins as well. I have recently used real-time methods to identify intrinsic dynamics of membrane protein complexes that enable functional conformational changes and are enhanced by cellular substrates. However, it is still unclear how these dynamics are controlled or regulated within membrane protein complexes. The long-term goal of my research program is to characterize dynamics within membrane protein complexes that regulate folding and assembly in biological membranes as well as communication across the phospholipid bilayer. Understanding the real-time dynamics of efflux pump assembly and function will provide insight into how bacteria respond to antibiotic stress and develop resistance, but also deepen our general knowledge of how membrane protein complexes fold, assemble, and function in a lipid bilayer. Accordingly, my comprehensive research program will study membrane protein complexes using multidrug efflux pumps as model systems, and, in the next five years, I will focus on two specific aims: 1) learn how efflux pumps are assembled in biological membranes during ongoing protein synthesis, and 2) characterize the structural dynamics of efflux pumps that drive and regulate antibiotic efflux. By understanding the real-time dynamics of membrane-protein complexes, we can hope to someday predict the effects of disease-causing mutations in advance, or fuel rational design of next-generation therapeutics targeting these complexes.