School of Mathematics & Physics, Hebei University of Engineering, Handan 056038, China.
Medical College, Hebei University of Engineering, Handan 056038, China.
J Phys Chem B. 2024 Sep 26;128(38):9074-9085. doi: 10.1021/acs.jpcb.4c02325. Epub 2024 Sep 14.
Metastasis of breast cancer is the main cause of death for patients with breast cancer. The interaction between metadherin (MTDH) and staphylococcal nuclease domain 1 (SND1) plays a pivotal role in promoting breast cancer development. However, the binding details between MTDH and SND1 remain unclear. In this study, we employed all-atom molecular dynamics simulations (MDs) and conducted binding energy calculations to investigate the binding details and the impact of key residue mutations on binding. The mutations in key residues have not significantly affected the overall stability of the structure and the fluctuation of residues near the binding site; they have exerted a substantial impact on the binding of SND1 and MTDH peptide. The electrostatic interactions and van der Waals interactions play an important role in the binding of SND1 and the MTDH peptide. The mutations in the key residues have a significant impact on electrostatic and van der Waals interactions, resulting in weakened binding. The energy contributions of key residues mainly come from the electrostatic energy and van der Waals interactions of the side chain. In addition, the key residues form an intricate and stable network of hydrogen bonds and salt-bridge interactions with the MTDH peptide. The mutations in key residues have directly disrupt the interactions formed between SND1 and MTDH peptide, consequently leading to changes in the binding mode of the MTDH peptide. These analyses unveil the detailed atomic-level interaction mechanism between SND1 and the MTDH peptide, providing a molecular foundation for the development of antibreast cancer drugs.
乳腺癌转移是乳腺癌患者死亡的主要原因。癌基因 MTDH 与 SND1 的相互作用在促进乳腺癌的发展中起着关键作用。然而，MTDH 与 SND1 的结合细节仍不清楚。在这项研究中，我们采用全原子分子动力学模拟（MDs）并进行结合能计算，以研究结合细节以及关键残基突变对结合的影响。关键残基的突变并没有显著影响结构的整体稳定性和结合部位附近残基的波动；它们对 SND1 和 MTDH 肽的结合有很大的影响。静电相互作用和范德华相互作用在 SND1 和 MTDH 肽的结合中起着重要作用。关键残基的突变对静电相互作用和范德华相互作用有显著影响，导致结合减弱。关键残基的能量贡献主要来自侧链的静电能和范德华相互作用。此外，关键残基与 MTDH 肽形成了一个复杂而稳定的氢键和盐桥相互作用网络。关键残基的突变直接破坏了 SND1 和 MTDH 肽之间形成的相互作用，从而导致 MTDH 肽的结合模式发生变化。这些分析揭示了 SND1 与 MTDH 肽之间详细的原子级相互作用机制，为开发抗乳腺癌药物提供了分子基础。
