Biophysics and Nanoscience Centre, DEB, Università della Tuscia, Largo dell'Università, 01100 Viterbo, Italy.
Int J Mol Sci. 2022 Oct 20;23(20):12636. doi: 10.3390/ijms232012636.
The conformational heterogeneity of the p53 tumor suppressor, the wild-type (p53wt) and mutated forms, was investigated by a computational approach, including the modeling and all atoms of the molecular dynamics (MD) simulations. Four different punctual mutations (p53R175H, p53R248Q, p53R273H, and p53R282W) which are known to affect the DNA binding and belong to the most frequent hot-spot mutations in human cancers, were taken into consideration. The MD trajectories of the wild-type and mutated p53 forms were analyzed by essential dynamics to extract the relevant collective motions and by the frustration method to evaluate the degeneracy of the energy landscape. We found that p53 is characterized by wide collective motions and its energy landscape exhibits a rather high frustration level, especially in the regions involved in the binding to physiological ligands. Punctual mutations give rise to a modulation of both the collective motions and the frustration of p53, with different effects depending on the mutation. The regions of p53wt and of the mutated forms characterized by a high frustration level are also largely involved in the collective motions. Such a correlation is discussed also in connection with the intrinsic disordered character of p53 and with its central functional role.
采用计算方法，包括建模和分子动力学（MD）模拟的全原子模拟，研究了 p53 肿瘤抑制因子的构象异质性，包括野生型（p53wt）和突变型。考虑了四个已知影响 DNA 结合的不同点状突变（p53R175H、p53R248Q、p53R273H 和 p53R282W），它们属于人类癌症中最常见的热点突变。通过基本动力学分析野生型和突变型 p53 形式的 MD 轨迹，提取相关的集体运动，并通过挫折方法评估能量景观的简并度。我们发现，p53 的特点是广泛的集体运动，其能量景观表现出相当高的挫折水平，尤其是在与生理配体结合的区域。点状突变会引起 p53 集体运动和挫折的调制，具体影响取决于突变。p53wt 和突变形式的区域，其挫折水平较高，也广泛涉及集体运动。这种相关性也与 p53 的固有无序特征及其中心功能作用有关。
