Human Inducible Hsp70: Structures, Dynamics, and Interdomain Communication from All-Atom Molecular Dynamics...

Area of Science:

• Molecular Biology
• Structural Biology
• Biophysics

Background:

• The 70 kDa human heat shock protein (Hsp70) is a critical molecular chaperone.
• Hsp70 plays a role in protein folding and is implicated in misfolding diseases and cancer.
• Hsp70's function relies on an allosteric mechanism involving its nucleotide-binding domain (NBD) and substrate-binding domain (SBD).

Purpose of the Study:

• To generate and analyze models of human Hsp70.
• To investigate the dynamic transition between open and closed conformational states of Hsp70.
• To elucidate the mechanistic basis of Hsp70's allosteric regulation and chaperoning cycle.

Main Methods:

• Homology modeling based on Saccharomyces cerevisiae Hsp110 and Escherichia coli DnaK.
• All-atom molecular dynamics simulations in explicit solvent.
• Coarse-grained modeling and normal-mode analysis.

Main Results:

• Two stable Hsp70 models were obtained: an open SBD state and a closed SBD state.
• These states correlate with experimental data for ATP-Hsp70 (open) and ADP-Hsp70 (closed).
• Conformational transitions are driven by a limited set of collective modes involving both NBD and SBD.

Conclusions:

• The study provides mechanistic insights into Hsp70's allosteric mechanism and chaperoning cycle.
• Identified key subdomains and residues critical for the conformational changes.
• These findings contribute to understanding Hsp70's role in health and disease, potentially guiding therapeutic strategies.