Multivalent ligands for adaptive intracellular protein receptors (B09*)

在B9项目中，将开发柔性多价蛋白配体作为柔性多价蛋白相互作用的抑制剂，并研究其在细胞内的应用。作为靶蛋白，我们将研究两种类型的二价蛋白受体，FBP21的串联ww -结构域和SYK-和ZAP70激酶的串联SH2结构域。细胞渗透性多价肽聚合物将通过功能肽、转运肽和荧光团在载体聚合物上的模块化偶联来制备。设计肽聚合物的参数将来自几种不同生物相容性聚合物的结合特性的比较。相关的记录参数包括结合自由能的焓和熵贡献、相互作用的化学计量以及多价配体-蛋白质复合物的聚集行为。构建优化的多价聚合物配体的结论将从C2 （Weber）进行的分子动力学模拟中得出，并将随后在功能生物学实验中受到挑战。

In project B9 flexible multivalent protein ligands will be developed as inhibitors of flexible multvalent protein-protein interactions and investigated in intracellular applications. As target proteins we will study two types of bivalent protein receptors, the tandem-WW-domain of FBP21 and the tandem SH2 domains of SYK- and ZAP70 kinases. Cell-permeable multivalent peptide polymers will be prepared by modular coupling of functional peptides, transport peptides, and fluorophores onto carrier polymers. Parameters for the design of peptide polymers will be derived from a comparison of the binding properties of several different biocompatible polymers. Relevant recorded parameters include the enthalpic and entropic contributions to the free energy of binding, the stoichiometry of the interaction and the aggregation behavior of the multivalent ligand-protein complexes. Conclusions for the construction of optimized multivalent polymeric ligands will be derived from molecular dynamics simulations conducted in C2 (Weber) and will be subsequently challenged in functional biological experiments.