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 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.
- Alessandro Barducci
- Paolo De Los Rios
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Arup K Chakraborty, Massachusetts Institute of Technology, United States
- Received: May 15, 2019
- Accepted: December 17, 2019
- Accepted Manuscript published: December 17, 2019 (version 1)
© 2019, Assenza et al.
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