Efficient conversion of chemical energy into mechanical work by Hsp70 chaperones

• DOI: 10.7554/elife.48491
• Publication Date: 2019-12-17T13:00:14Z
• Authors: Salvatore Assenza; Alberto Stefano S...; Ruth Kellner; Benjamin Schuler; Paolo De Los Rios; Alessandro Barducci
• Keywords: 0301 basic medicine; substrate-binding; QH301-705.5; Science; 610 Medicine & health; system; Molecular Dynamics Simulation; Physics of Living Systems; Hsp70; 03 medical and health sciences; Adenosine Triphosphate; 1300 General Biochemistry, Genetics and Molecular Biology; 2400 General Immunology and Microbiology; chemical energy; 10019 Department of Biochemistry; chaperones; HSP70 Heat-Shock Proteins; Biology (General); Adenosine Triphosphatases; Hydrolysis; molecular chaperones; Q; R; 2800 General Neuroscience; Física; Biomolecules (q-bio.BM); dynamics; mechanical work; non-equilibrium thermodynamics; [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics; ATP; Kinetics; Quantitative Biology - Biomolecules; Models, Chemical; FOS: Biological sciences; 570 Life sciences; biology; Medicine; Thermodynamics; molecular simulations; Algorithms; Molecular Chaperones

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.