Effects of macromolecular crowding on large-scale conformational transitions in proteins

Macromolecular crowding is known to impact various aspects of protein folding, including native state stability and folding rate. Much less is known about crowding effects on fold switching, i.e., the reversible structural transformations between different folds, which occurs in some proteins. Taking a coarse-grained simulation approach, we study how crowding affects fold propensities in the mutationally driven switch between the GA and GB folds of protein G. We find that the addition of crowders causes a shift in the relative population of the two folds, favoring GB. Our analysis demonstrate that the population shift is largely due to the presence of disordered tail regions, which are present only in the GA fold. We also explore whether the shift in relative population can be understood from crowding induced changes to the native state stabilities of the corresponding single fold proteins.