Forces Driving Membrane Protein Folds

Project Summary 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 lag far behind. The knowledge gained from soluble protein studies cannot simply be transferred to inferences about 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, quantify backbone hydrogen bond strengths, and expand our repertoire of membrane protein folding models to include those with an a-helical secondary structure. These efforts will be complemented by molecular simulations and other solution biophysics interrogations as needed. 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.