Understanding how proteins fold is a central quest in biology. Studied for over 50 years, investigations of soluble protein folding have proven invaluable for dissecting the molecular basis of a multitude of diseases. By comparison, folding studies of membrane proteins (MPs) lag far behind. The knowledge gained from soluble protein studies cannot simply be transferred to inferences about MPs because their solvents are different. The balance of forces encoding a MP embedded in a lipid bilayer must be distinct from that of soluble proteins in water. Our research efforts contribute to filling this key gap in the understanding the physical chemistry of membrane proteins. We will experimentally determine of energetic forces stabilizing membrane proteins along the steeply changing polarity gradient of the phospholipid bilayer interface. These efforts will be complemented by molecular simulations and mathematic systems modeling. In addition, we aim to incorporate novel techniques to our toolbox to address the energetic importance of backbone hydrogen bonds in transmembrane proteins. Our results have broad ranging impact in the field at large through contributions to information databases used in training computational algorithms and by their incorporation in physically realistic mechanisms for protein folding catalysis by cellular machines.
This discovery project will develop a fundamental understanding of the forces underlying folds and functions of membrane proteins. The knowledge gained from this research will contribute to the design of therapeutics to combat protein misfolding diseases, will be useful in the computational modeling of protein structures and of drug-binding to protein structures, and will inform on the design of proteins with novel functions.
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