Institute of Space Science and Technology, Nanchang University, Xuefu Avenue 999, Nanchang City 330031, China.
Department of Physics, School of Sciences, Nanchang University, Xuefu Avenue 999, Nanchang City 330031, China.
Phys Chem Chem Phys. 2021 Oct 20;23(40):23032-23041. doi: 10.1039/d1cp03094a.
p53 mutant aggregation can lead to loss-of-function (LoF), dominant-negative (DN) and gain-of-function (GoF) effects, involving in tumor growth. Finding inhibition methods of p53 mutant aggregation is a key step for developing new therapeutics against aggregation-associated cancers. Recent studies have shown that a cell-permeable peptide, ReACp53, can inhibit aggregation of the p53 mutant and restore p53 nuclear function as a transcriptional factor, showing extraordinary therapeutic potential. However, the molecular mechanism underlying the inhibition of p53 mutant aggregation by the ReAp53 peptide is unclear. In this work, we used all-atom molecular dynamics (MD) simulations to investigate the effect of ReACp53 peptide on the structural and dynamic properties of the p53 core domain (p53C) of the aggregation-prone R175H mutant. Our simulations revealed that the ReACp53 peptide can stabilize the ordered secondary structure and decrease the flexibility of disordered loops of the R175H mutant through increasing the intra-interactions of p53C. Moreover, we found that ReACp53 peptide specifically binds to the fragment (residues 180-233) of the R175H mutant through strong hydrophobic interactions with residues L188 and L201 and a salt bridge or hydrogen bond formation with residues D186, E198, D204, E221 and E224. The specific binding pattern protects the aggregation-prone fragment (residues 182-213) from exposure to water. Hence, we suggested that the ReACp53 peptide inhibits aggregation of the R175H mutant by restoring the wild-type conformation from an aggregation-prone state and reducing the exposure of the aggregation-prone segment. These results provide molecular mechanistic insight into inhibition of the ReACp53 peptide on amyloid aggregation of the R175H mutant.
p53 突变体聚集会导致功能丧失（Loss-of-Function，LoF）、显性负（Dominant-Negative，DN）和获得功能（Gain-of-Function，GoF）效应，从而参与肿瘤生长。寻找抑制 p53 突变体聚集的方法是开发针对聚集相关癌症的新疗法的关键步骤。最近的研究表明，一种细胞穿透肽 ReACp53 可以抑制 p53 突变体的聚集并恢复其作为转录因子的核功能，显示出非凡的治疗潜力。然而，ReAp53 肽抑制 p53 突变体聚集的分子机制尚不清楚。在这项工作中，我们使用全原子分子动力学（MD）模拟研究了 ReACp53 肽对易于聚集的 R175H 突变体的 p53 核心结构域（p53C）的结构和动态特性的影响。我们的模拟表明，ReACp53 肽可以通过增加 p53C 的内相互作用来稳定有序的二级结构并降低无序环的灵活性。此外，我们发现 ReACp53 肽通过与残基 L188 和 L201 形成强疏水性相互作用，并与残基 D186、E198、D204、E221 和 E224 形成盐桥或氢键形成，特异性结合到 R175H 突变体的片段（残基 180-233）。这种特异性结合模式可防止易于聚集的片段（残基 182-213）暴露于水中。因此，我们认为 ReACp53 肽通过从易于聚集的状态恢复野生型构象并减少易于聚集的片段的暴露来抑制 R175H 突变体的聚集。这些结果为 ReACp53 肽抑制 R175H 突变体的淀粉样聚集提供了分子机制上的见解。
