Molecular dynamics simulations shows real-time lid opening in Hsp70 chaperone

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• Heat shock protein 70 (Hsp70) and its bacterial homolog DnaK are essential molecular chaperones involved in protein folding and homeostasis.
• Hsp70 is a 70 kDa protein with three domains, critical for cellular proteostasis and particularly important for cancer cell survival, making it a potential therapeutic target.

Purpose of the Study:

• To investigate the dynamics of the Hsp70 substrate-binding domain (SBD) and Lid domain using molecular dynamics simulations.
• To characterize the allosteric motion within the Hsp70 SBD/Lid machinery.
• To assess the effect of the small molecule PET16 on Hsp70 dynamics.

Main Methods:

• Molecular dynamics (MD) simulations were employed to study the Hsp70 SBD/Lid complex.
• Simulations were performed on the apo-form and in the presence of the PET16 molecule.
• Analysis focused on the conformational changes and dynamics of the Lid domain.

Main Results:

• The apo-form of the Hsp70 dimer displayed an unexpected opening of the entire Lid domain.
• The observed open structure configuration significantly differed from previously reported structures (PDB 4JN4).
• MD simulations indicated that the Lid domain possesses greater dynamical flexibility than suggested by experimental structural biology.

Conclusions:

• The enhanced flexibility of the Hsp70 Lid domain provides valuable insights for future drug discovery efforts targeting Hsp70.
• The PET16 molecule showed weak binding, and its precise impact on Hsp70 dynamics requires further investigation.