Assenza, SalvatoreSassi, Alberto StefanoKellner, RuthSchuler, BenjaminDe Los Rios, PaoloBarducci, Alessandro2020-02-232020-02-232020-02-232019-12-1710.7554/eLife.48491https://infoscience.epfl.ch/handle/20.500.14299/166452WOS:000512312000001Hsp70 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 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 effectively convert chemical energy into mechanical work close to physiological conditions.BiologyLife Sciences & Biomedicine - Other Topicsmolecular chaperonessubstrate-bindingdynamicssystemtext::journal::journal article::research article