DNA topoisomerase 2-binding protein 1 (Topbp1) plays a crucial role in activating the ataxia-telangiectasia mutated and rad3-related (ATR) complex to initiate DNA damage repair responses. For this process to occur, it is necessary for PHF8 to dissociate from Topbp1. Topbp1 binds to the acidic patch sequence (APS) of PHF8 through its C-terminal BRCT7/8 domain, and disrupting this interaction could be a promising strategy for cancer treatment. To investigate the dissociation process and binding pattern of BRCT7/8-PHF8, we employed enhanced sampling techniques, such as steered molecular dynamics (SMD) simulations and accelerated molecular dynamics (aMD) simulations, along with self-organizing maps (SOM) and time-resolved force distribution analysis (TRFDA) methodologies. Our results demonstrate that the dissociation of PHF8 from BRCT7/8 starts from the N-terminus, leading to the unfolding of the N-terminal helix. Additionally, we identified critical residues that play a pivotal role in this dissociation process. These findings provide valuable insights into the disassociation of PHF8 from BRCT7/8, which could potentially guide the development of novel drugs targeting Topbp1 for cancer therapy.

中文翻译：

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深入了解 BRCT7/8-PHF8 复合物的解离过程和结合模式


DNA 拓扑异构酶 2 结合蛋白 1 (Topbp1) 在激活共济失调毛细血管扩张突变和 rad3 相关 (ATR) 复合物以启动 DNA 损伤修复反应中发挥着至关重要的作用。为了发生这一过程，PHF8 必须与 Topbp1 解离。 Topbp1 通过其 C 端 BRCT7/8 结构域与 PHF8 的酸性补丁序列 (APS) 结合，破坏这种相互作用可能是一种有前景的癌症治疗策略。为了研究 BRCT7/8-PHF8 的解离过程和结合模式，我们采用了增强的采样技术，例如引导分子动力学 (SMD) 模拟和加速分子动力学 (aMD) 模拟，以及自组织图 (SOM) 和时间-分辨力分布分析（TRFDA）方法。我们的结果表明，PHF8 与 BRCT7/8 的解离从 N 末端开始，导致 N 末端螺旋展开。此外，我们还确定了在该解离过程中发挥关键作用的关键残基。这些发现为 PHF8 与 BRCT7/8 的解离提供了宝贵的见解，这可能指导开发针对 Topbp1 的癌症治疗新药物。