Efficient conversion of chemical energy into mechanical work by Hsp70 chaperones
Abstract
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.
Data availability
All the source data used for generating relevant figures (Fig1,2,2Supp1,4,5,6,1App) have been provided as supporting files.All the information necessary for reproducing the molecular simulations have been deposited in github (https://github.com/saassenza/Hsp70Unfoldase) and PLUMED NEST (plumID:19.076) repositories.
Article and author information
Author details
Funding
Agence Nationale de la Recherche (ANR-14-ACHN-0016)
- Alessandro Barducci
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (200020_163042)
- 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.
Reviewing Editor
- Arup K Chakraborty, Massachusetts Institute of Technology, United States
Publication history
- Received: May 15, 2019
- Accepted: December 17, 2019
- Accepted Manuscript published: December 17, 2019 (version 1)
- Version of Record published: February 4, 2020 (version 2)
Copyright
© 2019, Assenza et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Physics of Living Systems
Veins in vascular networks, such as in blood vasculature or leaf networks, continuously reorganize, grow or shrink, to minimize energy dissipation. Flow shear stress on vein walls has been set forth as the local driver for a vein’s continuous adaptation. Yet, shear feedback alone cannot account for the observed diversity of vein dynamics – a puzzle made harder by scarce spatiotemporal data. Here, we resolve network-wide vein dynamics and shear rate during spontaneous reorganization in the prototypical vascular networks of Physarum polycephalum. Our experiments reveal a plethora of vein dynamics (stable, growing, shrinking) where the role of shear is ambiguous. Quantitative analysis of our data reveals that (a) shear rate indeed feeds back on vein radius, yet, with a time delay of 1–3 min. Further, we reconcile the experimentally observed disparate vein fates by developing a model for vein adaptation within a network and accounting for the observed time delay. The model reveals that (b) vein fate is determined by parameters – local pressure or relative vein resistance – which integrate the entire network’s architecture, as they result from global conservation of fluid volume. Finally, we observe avalanches of network reorganization events that cause entire clusters of veins to vanish. Such avalanches are consistent with network architecture integrating parameters governing vein fate as vein connections continuously change. As the network architecture integrating parameters intrinsically arise from laminar fluid flow in veins, we expect our findings to play a role across flow-based vascular networks.
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- Physics of Living Systems
A combination of in toto imaging and theory suggests a new mechanism for the remodeling of veins in vascular networks.