1. Exploring the binding mechanism of a small molecular Hsp70-Bim PPI inhibitor through molecular dynamic simulation.
- Author
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Li, Xin, Wang, Yuying, Jiang, Maojun, Yin, Fangkui, Zhang, Hong, Yuan, Linjie, Liu, Jingjing, Wang, Xingyu, Wang, Ziqian, and Zhang, Zhichao
- Subjects
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DYNAMIC simulation , *CHRONIC myeloid leukemia , *PROTEIN-protein interactions , *MOLECULAR dynamics , *STARTLE reaction , *HEAT shock proteins , *BINDING sites - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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