Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203/8, 500 05 Hradec Králové, Czech Republic.
Division of Computational Chemistry, Department of Chemistry, Lund University, P.O. Box 124, 221 00 Lund, Sweden.
J Chem Theory Comput. 2024 Jul 23;20(14):5842-5853. doi: 10.1021/acs.jctc.4c00570. Epub 2024 Jul 7.
This study focuses on the intrinsically disordered regulatory domain of p53 and the impact of post-translational modifications. Through fully atomistic explicit water molecular dynamics simulations, we show the wealth of information and detailed understanding that can be obtained by varying the number of phosphorylated amino acids and implementing a restriction in the conformational entropy of the N-termini of that intrinsically disordered region. The take-home message for the reader is to achieve a detailed understanding of the impact of phosphorylation with respect to (1) the conformational dynamics and flexibility, (2) structural effects, (3) protein interactivity, and (4) energy landscapes and conformational ensembles. Although our model system is the regulatory domain p53 of the tumor suppressor protein p53, this study contributes to understanding the general effects of intrinsically disordered phosphorylated proteins and the impact of phosphorylated groups, more specifically, how minor changes in the primary sequence can affect the properties mentioned above.
本研究聚焦于 p53 的无规则调控结构域和翻译后修饰的影响。通过全原子显式水分子动力学模拟，我们展示了通过改变磷酸化氨基酸的数量并限制无规则结构域 N 端的构象熵，能够获得丰富的信息和详细的理解。对于读者来说，重要的是要实现对磷酸化影响的详细理解，具体包括：（1）构象动力学和灵活性；（2）结构效应；（3）蛋白质相互作用；（4）能量景观和构象集合。虽然我们的模型系统是肿瘤抑制蛋白 p53 的调控结构域 p53，但这项研究有助于理解无规则磷酸化蛋白的一般影响以及磷酸化基团的影响，更具体地说，就是如何通过改变一级序列中的微小变化来影响上述性质。
