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Exploring the binding mechanism of a small molecular Hsp70-Bim PPI inhibitor through molecular dynamic simulation

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Abstract

Context

The interface of Hsp70-Bim protein–protein interaction (PPI) has been identified as a specific target for Chronic Myeloid Leukemia (CML) therapy and the specific inhibitors were developed to exhibit in vivo anti-leukemia activities. Herein, we explored the binding mechanism of a Hsp70-Bim inhibitor, 6-(cyclohexylthio)-3-((2-morpholinoethyl) amino)-1-oxo-1H-phenalene-2-carbonitrile (S1g-6), to Hsp70 at the atomic level by MD simulation. TYR-149, THR-222, ALA-223, and GLY-224 on Hsp70 were identified as four key residues that contribute to Hsp70/S1g-6 complex. Moreover, the site mutation validation demonstrated the TYR-149 of Hsp70 is a “hot-spot” in the Hsp70-Bim PPI interface. These results could benefit the design of further inhibitors to occupy the Bim binding site on the Hsp70 surface.

Methods

The binding mechanism of S1g-6 and Hsp70 was predicted through the molecular dynamics (MD) method by Gromacs-2021.3. The MD simulation was performed with 100-ps NVT and 100-ps NPT ensemble, and the force field was chosen as the Charmm36 force field. The temperature was set as 300 K, the time step was 2 fs and the total MD simulation time was 500 ns.

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Data availability

The Hsp70 protein structure (4H5T) is available from https://www.pdbus.org/structure/4H5T. The MD simulation trajectories analyzed in this work will be shared upon request.

Abbreviations

Hsp70:

Heat-shock protein 70

Bim:

Bcl-2-interacting mediator of cell death

PPI:

Protein–protein interaction

MD:

Molecular dynamic

CML:

Chronic Myeloid Leukemia

TKI:

Tyrosine kinase inhibitor

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Funding

This research was supported by the National Natural Science Foundation of China (82273778, 82270186, and 82073703), and the Fundamental Research Funds for the Central University (DUT22YG223, DUT22YG106 and 2022ZXYG46).

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Authors and Affiliations

  1. Cancer Hospital of Dalian University of Technology, School of Chemistry, Dalian University of Technology, Dalian, Liaoning, China

    Xin Li, Maojun Jiang, Fangkui Yin, Hong Zhang, Linjie Yuan, Ziqian Wang & Zhichao Zhang

  2. Cancer Hospital of Dalian University of Technology, School of Life Science and Technology, Dalian University of Technology, Dalian, Liaoning, China

    Yuying Wang, Jingjing Liu & Xingyu Wang

Authors
  1. Xin Li
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  2. Yuying Wang
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  3. Maojun Jiang
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  4. Fangkui Yin
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  5. Hong Zhang
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  6. Linjie Yuan
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  7. Jingjing Liu
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  8. Xingyu Wang
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  9. Ziqian Wang
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  10. Zhichao Zhang
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Contributions

Xin Li and Xingyu Wang did the molecular dynamics simulations of this paper; Yuying Wang, Maojun Jiang, and Linjie Yuan did protein expression and purification of this paper; Hong Zhang and Jingjing Liu did fluorescence Polarization Assays and analyzed the data; Fangkui Yin prepared figures; Xin Li, Ziqian Wang, and Zhichao Zhang wrote this article.

Corresponding authors

Correspondence to Ziqian Wang or Zhichao Zhang.

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Cite this article

Li, X., Wang, Y., Jiang, M. et al. Exploring the binding mechanism of a small molecular Hsp70-Bim PPI inhibitor through molecular dynamic simulation. J Mol Model 30, 71 (2024). https://doi.org/10.1007/s00894-024-05874-8

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  • DOI: https://doi.org/10.1007/s00894-024-05874-8

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