Protein recognition for modular domains

描述(申请人提供)：蛋白质在几乎所有的生物过程中都是必不可少的，蛋白质与其相互作用的伙伴之间的相互作用在起作用的细胞中起着关键作用。由于破坏蛋白质相互作用的突变会导致许多疾病，了解蛋白质识别的生化机制对于破译蛋白质相互作用网络和设计针对蛋白质靶点的高效药物具有重要意义。我们的长期目标是开发描述蛋白质结合特异性的理论模型，并可靠地预测蛋白质之间的相互作用。在拟议的项目中，我们有以下具体目标。目的1，我们将开发一种结合计算机建模和生物信息学分析的计算方法来表征模块结构域与其多肽配体之间的相互作用界面。我们将在几个模块结构域上测试这种方法，包括与特定肽序列结合的SH3、SH2和PDZ结构域。目的2，我们将系统地预测酵母基因组中所有酵母SH3结构域的相互作用多肽。目的3，我们将在体外对预测进行实验验证，以评估计算方法的性能。我们还将进行体内实验，以检验一组选定的结构域-多肽相互作用的生物学意义。 与公共卫生相关：蛋白质-蛋白质相互作用在细胞中发挥关键作用，而破坏这些相互作用的突变会导致许多疾病。因此，了解蛋白质识别的生化机制是很重要的。

DESCRIPTION (provided by applicant): Protein is essential for almost every biological process and the interaction between proteins and their interacting partners play critical roles in the functioning cells. Since mutations that disrupt the protein-protein interactions result in many diseases, it is important to understand the biochemical mechanisms of protein recognition, which is important for deciphering protein interaction network and designing potent drugs with high specificity against protein targets. Our long term goal is to develop theoretical models for describing protein binding specificity and reliably predict protein-protein interactions. In the proposed project, we have the following specific aims. Aim 1, we will develop a computational method that combines computer modeling and bioinformatics analysis to characterize the interaction interface between modular domains and their peptide ligands. We will test this method on several modular domains including SH3, SH2 and PDZ domains that bind to specific peptide sequences. Aim 2, we will systematically predict interacting peptides in the yeast genome of all yeast SH3 domains. Aim 3, we will experimentally validate the predictions in vitro to assess the performance of the computational method. We will also conduct in vivo experiments to examine the biological significance of a set of selected domain-peptide interactions. PUBLIC HEALTH RELEVANCE: Protein-protein interactions play critical roles in the cell and mutations that disrupt these interactions result in many diseases. It is therefore important to understand the biochemical mechanisms of protein recognition.