  Hsp70 molecular chaperones are abundant ATP-dependent nanomachines that
actively reshape non-native, misfolded proteins and assist a wide variety of
essential cellular processes. Here we combine complementary
computational/theoretical approaches to elucidate the structural and
thermodynamic details of the chaperone-induced expansion of a substrate
protein, with a particular emphasis on the critical role played by ATP
hydrolysis. We first determine the conformational free-energy cost of the
substrate expansion due to the binding of multiple chaperones using
coarse-grained molecular simulations. We then exploit this result to implement
a non-equilibrium rate model which estimates the degree of expansion as a
function of the free energy provided by ATP hydrolysis. Our results are in
quantitative agreement with recent single-molecule FRET experiments and
highlight the stark non-equilibrium nature of the process, showing that Hsp70s
are optimized to convert effectively chemical energy into mechanical work close
to physiological conditions.
