  Molecular chaperones are ATP-consuming biological machines, which facilitate
the folding of proteins and RNA molecules that are kinetically trapped in
misfolded states for long times. Unassisted folding occurs by the kinetic
partitioning mechanism according to which folding to the native state, with low
probability as well as misfolding to one of the many metastable states, with
high probability, occur rapidly on similar time scales. GroEL is an all-purpose
stochastic machine that assists misfolded substrate proteins (SPs) to fold. The
RNA chaperones (CYT-19) help the folding of ribozymes that readily misfold.
GroEL does not interact with the folded proteins but CYT-19 disrupts both the
folded and misfolded ribozymes. Despite this major difference, the Iterative
Annealing Mechanism (IAM) quantitatively explains all the available
experimental data for assisted folding of proteins and ribozymes. Driven by ATP
binding and hydrolysis and GroES binding, GroEL undergoes a catalytic cycle
during which it samples three allosteric states, referred to as T (apo), R (ATP
bound), and R'' (ADP bound). In accord with the IAM predictions, analyses of
the experimental data shows that the efficiency of the GroEL-GroES machinery
and mutants is determined by the resetting rate $k_{R''\rightarrow T}$, which
is largest for the wild type GroEL. Generalized IAM accurately predicts the
folding kinetics of Tetrahymena ribozyme and its variants. Chaperones maximize
the product of the folding rate and the steady state native state fold by
driving the substrates out of equilibrium. Neither the absolute yield nor the
folding rate is optimized.
