Assessment of Protein Folding/Solubility in Live Cells

The folding of a protein to its final native state involves a series of complex steps of intra- and intermolecular interactions between the nascent polypeptide chain, its solvent environment, and the quality control machinery of the cell (1). These steps are often halting, as the unfolded protein visits a series of intermediates states en route to its final native structure. In the cell, undesirable reactions such as aggregation and proteolytic degradation compete for these folding intermediates, shuffling them off the productive folding pathway (see Fig. 1). Thus, in order to properly fold, many proteins require the oversight of molecular chaperones that bias intermediates towards productive folding rather than off-pathway self-associations (2). Changes in this delicate balance between on- and off-pathway reactions have ramifications both for human health and the study of proteins of structural interest or of commercial utility.