p53 is a transcription factor with intrinsically disordered regions that plays an essential role in many cellular processes. As a tumor suppressor, the dysfunction of p53 causes various cancers. p53 can be activated by binding with cofactors in the cell due to stresses or DNA damages. The N-terminal transactivation domain (TAD) of p53 can regulate cell apoptosis by interacting with its binding partners, such as the transcriptional adaptor zinc-binding 2 (Taz2) domain of p300, and cofactors, i.e. cyclic-AMP response element-binding protein (CREB)-binding protein (CBP). The experimentally solved structure of p300 Taz2 and p53 TAD2 has provided insights into the interactions that potentially lead to the structural changes of p53 TAD2 and stabilize the complex. To explore the structural changes as well as the residues that lead to such changes from an isolated state to a bound state in p53 TAD2, we used all-atom molecular dynamics (MD) to simulate two different systems: (1) the p300 Taz2–p53 TAD2 complex and (2) isolated p53 TAD2 (residues 35–59). Although still largely unstructured, residues across the p53 TAD2 contribute significantly to stabilizing the binding between p300 Taz2 and p53 TAD2. Our results suggest that the binding affinity of the p300 Taz2–p53 TAD2 complex originates from hydrophobic and electrostatic interactions. The results are in agreement with previous reports and experimental data. By comparing the two simulated systems, our results not only demonstrate the structural changes of p53 TAD2 after binding with Taz2 but also identify the key residues leading to such changes. We also identify the critical residues that can provide insight into the interaction network between p300 Taz2 and p53 TAD2.

中文翻译：

---

p53 TAD2 与 p300 Taz2 结合后结构和灵活性的变化

p53 是一种具有内在无序区域的转录因子，在许多细胞过程中起着重要作用。作为一种肿瘤抑制因子，p53 的功能障碍会导致各种癌症。由于压力或 DNA 损伤，p53 可以通过与细胞中的辅因子结合而被激活。p53 的 N 端反式激活结构域 (TAD) 可以通过与其结合伙伴相互作用来调节细胞凋亡，例如 p300 的转录接头锌结合 2 (Taz2) 结构域和辅助因子，即环 AMP 反应元件结合蛋白(CREB) 结合蛋白 (CBP)。p300 Taz2 和 p53 TAD2 的实验解析结构提供了对可能导致 p53 TAD2 结构变化和稳定复合物的相互作用的见解。为了探索结构变化以及导致 p53 TAD2 中从孤立状态到束缚状态的这种变化的残基，我们使用全原子分子动力学 (MD) 来模拟两个不同的系统：(1) p300 Taz2– p53 TAD2 复合物和 (2) 分离的 p53 TAD2（残基 35-59）。尽管在很大程度上仍然是非结构化的，但 p53 TAD2 上的残基对稳定 p300 Taz2 和 p53 TAD2 之间的结合有很大贡献。我们的结果表明 p300 Taz2-p53 TAD2 复合物的结合亲和力源于疏水和静电相互作用。结果与之前的报道和实验数据一致。通过比较两个模拟系统，我们的结果不仅证明了 p53 TAD2 在与 Taz2 结合后的结构变化，而且还确定了导致这种变化的关键残基。