Gao Meng, Han Yue, Zeng Yifan, Su Zhengding, Huang Yongqi
Key Laboratory of Industrial Fermentation, Ministry of Education, Wuhan, China; Hubei Key Laboratory of Industrial Microbiology, Department of Biological Engineering, Wuhan, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China.
Key Laboratory of Industrial Fermentation, Ministry of Education, Wuhan, China; Hubei Key Laboratory of Industrial Microbiology, Department of Biological Engineering, Wuhan, China; National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, China.
Biophys J. 2021 Aug 3;120(15):2998-3007. doi: 10.1016/j.bpj.2021.06.021. Epub 2021 Jun 30.
Protein-protein interactions underlie many critical biology functions, such as cellular signaling and gene expression, in which electrostatic interactions can play a critical role in mediating the specificity and stability of protein complexes. A substantial portion of proteins are intrinsically disordered, and the influences of structural disorder on binding kinetics and thermodynamics have been widely investigated. However, whether the effect of electrostatic steering depends on structural disorder remains unexplored. In this work, we addressed the consequence of introducing intrinsic disorder in the electrostatic steering of the E3/Im3 complex using molecular dynamics simulation. Our results recapitulated the experimental observations that the responses of stability and kinetics to salt concentration for the ordered E3/Im3 complex were larger than those for the disordered E3/Im3 complex. Mechanistic analysis revealed that the native contact interactions involved in the encounter state and the transition state were essentially identical for both ordered and disordered E3. Therefore, the observed difference in electrostatic steering between ordered E3 and disordered E3 may result from their difference in conformation rather than their difference in binding mechanism. Because charged residues are frequently involved in protein-protein interactions, our results suggest that increasing structural disorder is expected to generally modulate the effect of electrostatic steering.
蛋白质-蛋白质相互作用是许多关键生物学功能的基础，如细胞信号传导和基因表达，其中静电相互作用在介导蛋白质复合物的特异性和稳定性方面可能发挥关键作用。相当一部分蛋白质是内在无序的，并且结构无序对结合动力学和热力学的影响已得到广泛研究。然而，静电引导的效应是否取决于结构无序仍未得到探索。在这项工作中，我们使用分子动力学模拟研究了在E3/Im3复合物的静电引导中引入内在无序的后果。我们的结果重现了实验观察结果，即有序的E3/Im3复合物对盐浓度的稳定性和动力学响应大于无序的E3/Im3复合物。机理分析表明，有序和无序的E3在相遇状态和过渡状态中涉及的天然接触相互作用基本相同。因此，观察到的有序E3和无序E3之间静电引导的差异可能是由于它们构象的差异，而不是它们结合机制的差异。由于带电残基经常参与蛋白质-蛋白质相互作用，我们的结果表明，增加结构无序有望普遍调节静电引导的效应。
