Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) are subject to phosphorylation as a means to modulate their interactions and functions. Toward understanding the relationship between phosphorylation in IDRs and specific functional outcomes, we must consider how phosphorylation affects the IDR conformational ensemble. Various experimental techniques are suited to interrogate the features of IDR ensembles; molecular simulations can provide complementary insights and even illuminate ensemble features that may be experimentally inaccessible. Therefore, we sought to expand the tools available to study phosphorylated IDRs by all-atom Monte Carlo simulations. To this end, we implemented parameters for phosphoserine (pSer) and phosphothreonine (pThr) into the OPLS version of the continuum solvent model, ABSINTH, and assessed their performance in all-atom simulations compared with published findings. We simulated short (<20 residues) and long (>80 residues) phospho-IDRs that, collectively, survey both local and global phosphorylation-induced changes to the ensemble. Our simulations of four well-studied phospho-IDRs show near-quantitative agreement with published findings for these systems via metrics including changes to radius of gyration, transient helicity, and persistence length. We also leveraged the inherent advantage of sequence control in molecular simulations to explore the conformational effects of diverse combinations of phospho-sites in two multiphosphorylated IDRs. Our results support and expand on previous observations that connect phosphorylation to changes in the IDR conformational ensemble. Herein, we describe phosphorylation as a means to alter sequence chemistry, net charge and charge patterning, and intramolecular interactions, which can collectively modulate the local and global IDR ensemble features.

中文翻译：

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无序蛋白的磷酸化可调节局部和全局分子内相互作用


蛋白质翻译后修饰（如磷酸化）是多种细胞功能的重要调节信号。特别是，固有无序的蛋白质区域 （IDR） 会受到磷酸化的影响，作为调节其相互作用和功能的一种手段。为了了解 IDR 磷酸化与特定功能结果之间的关系，我们必须考虑磷酸化如何影响 IDR 构象集合。各种实验技术适用于询问 IDR 集合的特征;分子模拟可以提供互补的见解，甚至可以阐明实验可能无法获得的集合特征。因此，我们试图扩展可用于通过全原子蒙特卡洛模拟研究磷酸化 IDR 的工具。为此，我们将磷酸丝氨酸 （pSer） 和磷酸苏氨酸 （pThr） 的参数实施到连续溶剂模型的 OPLS 版本 ABSINTH 中，并与已发表的研究结果相比评估了它们在全原子模拟中的性能。我们模拟了短 （<20 残基） 和长 （>80 残基） 磷酸化 IDR，它们共同研究了局部和全局磷酸化诱导的集合变化。我们对四种经过充分研究的磷酸化 IDR 的模拟显示，通过包括回转半径、瞬态螺旋度和持久性长度的变化在内的指标，这些系统与已发表的发现近乎定量一致。我们还利用分子模拟中序列控制的固有优势来探索两个多磷酸化 IDR 中磷酸位点不同组合的构象效应。我们的结果支持并扩展了先前的观察结果，这些观察结果将磷酸化与 IDR 构象集合的变化联系起来。 在本文中，我们将磷酸化描述为一种改变序列化学、净电荷和电荷模式以及分子内相互作用的手段，这可以共同调节局部和全局 IDR 集合特征。