How phosphorylation affects peptide interaction with adaptor domains

蛋白质-蛋白质相互作用（PPIs）是生物细胞中大多数过程的基本相关，因此是大量实验和计算工作的焦点。值得注意的是，ppi也可能受到相关蛋白翻译后修饰（如磷酸化）的强烈影响，这些修饰可能有利于或不利于特定复合物的形成。在这个项目中，我们将通过分子动力学模拟来分析适配器结构域与磷酸化和未磷酸化肽结合物的相互作用。我们将在第一个资助阶段成功地描述这种结合过程，在那里我们通过类似的模拟研究了磷酸化/非磷酸化肽与hPTP1E蛋白的PDZ2结构域和MAGI1蛋白的PDZ1结构域的结合。在这个项目中，我们将首先通过校准实验结合亲和力来纠正磷酸盐参数的轻微不准确性。在与结构生物学小组的合作中，我们的目标是建立一个机制描述，为什么磷酸化的氨基酸可以根据磷酸基团沿肽序列的位置而有利于或不有利于肽与PDZ结构域的结合。然后将这些MD模拟扩展到MAP1LC3A ATG8域和TSG101 UEV域。最后，我们将开发一个分类器，可以预测给定的PDZ结构域的原子结构和与之结合的肽的序列，无论是磷酸化还是非磷酸化的变体结合更强，以及自由结合焓差的回归模型。

Protein-protein interactions (PPIs) are of fundamental relevance for most processes in biological cells and hence the focus of considerable experimental and computational efforts. Notably, PPIs may also be strongly affected by post-translational modifications of the involved proteins such as phosphorylation that may either favor or disfavor formation of a particular complex. In this project, we will analyze interactions of adaptor domains with phosphorylated and unphosphorylated peptide binders by means of molecular dynamics simulations. We will build on the successful characterization of such binding processes in a first funding phase, where we studied binding of phospho/non-phospho peptides to the PDZ2 domain of the hPTP1E protein and to the PDZ1 domain of the MAGI1 protein by comparable simulations. In this project, we will at first correct slight inaccuracies of the phosphate parameters by calibration against experimental binding affinities. In collaboration with a structural biology group, we aim at establishing a mechanistic description why phosphorylated amino acids can either favor or disfavor binding of the peptide to PDZ domains depending on where the phosphate group is placed along the peptide sequence. These MD simulations will then be extended to MAP1LC3A ATG8 domains and TSG101 UEV domains. Finally, we will develop a classifier that can predict, for a given atomistic structure of a PDZ domain and for the sequence of a peptide binding to it, whether either its phosphorylated or non-phosphorylated variant binds more strongly, and a regression model for the difference in free binding enthalpy.