Efficient conversion of chemical energy into mechanical work by Hsp70 chaperones

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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.

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Salvatore Assenza

Laboratory of Food and Soft Materials, ETH Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Alberto Stefano Sassi

Institute of Physics, School of Basic Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.
Ruth Kellner

Department of Biochemistry, University of Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Benjamin Schuler

Department of Biochemistry, University of Zurich, Zurich, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5970-4251
Paolo De Los Rios

Institute of Physics, School of Basic Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5394-5062
Alessandro Barducci

Centre de Biochimie Structurale U1054, INSERM, Montpellier, France

For correspondence
alessandro.barducci@cbs.cnrs.fr

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1911-8039

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.

Copyright

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.