Efficient conversion of chemical energy into mechanical work by Hsp70 chaperones

TL;DR

This study combines computational and theoretical methods to understand how Hsp70 chaperones convert ATP energy into mechanical work, expanding substrate proteins efficiently in living cells.

Contribution

It provides a detailed thermodynamic and structural analysis of Hsp70-induced substrate expansion, emphasizing the role of ATP hydrolysis and non-equilibrium dynamics.

Findings

Quantitative agreement with single-molecule FRET experiments

Hsp70s are optimized for efficient energy conversion near physiological conditions

The process is inherently non-equilibrium, driven by ATP hydrolysis

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 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.