Iterative annealing mechanism for protein and RNA chaperones

Molecular chaperones are machines that consume copious amounts of ATP to facilitate the folding of misfolded proteins or RNA to their functionally competent native states by driving them out of equilibrium. Because the folding landscapes of biomolecules with complex native state topology are rugged, consisting of multiple minima that are separated by large free energy barriers, folding occurs by the kinetic partitioning mechanism according to which only a small fraction of the molecules reach the folded state in biologically viable times. The remaining fraction is kinetically trapped in a manifold of misfolded states. Folding of such recalcitrant proteins and RNA requires chaperones. Although the protein and RNA chaperones are profoundly different in their structure and action, the principles underlying their activity to produce the folded structures can be understood using a unified theoretical framework based on iterative annealing mechanism. Our theory, which quantitatively explains a number of experimental data, shows that both these machines have evolved to maximize the steady-state yield on biological times. Strikingly, the theory predicts that only at a moderate level of RNA chaperone activity is the yield of the self-splicing pre-RNA maximized in vivo.