Aromatic Interactions in Nucleotide/Carbohydrate Binding

分子设计是评估我们对分子识别事件和非共价相互作用的知识的有力工具。通过分子受体的设计，我们目前对分子识别的认识已经有了很大的进步，从早期的冠醚到目前的阴离子受体。通过蛋白质的从头设计，人们对蛋白质折叠和结构的复杂方面也有了很多了解。从概念上讲，蛋白质从头设计也是一种强有力的方法，用于定义生物分子识别中的关键元素。在这个计划中，我们的目标是利用设计的结构化肽来研究生物分子识别方面，包括蛋白质-核酸和蛋白质-碳水化合物 识别.我们已经开发了一种β-发夹肽，其通过芳香堆积和静电相互作用的组合与核苷酸和ssDNA结合。我们打算利用这个系统来调查方面的序列和结构选择性识别的DNA。关于结构选择性识别，我们将研究堆叠相互作用在双链体DNA中烷基化碱基的选择性识别中的作用，模拟糖基化酶和mRNA帽结合蛋白。这些研究在化学疗法、基因表达控制和抗病毒治疗方面具有潜在的应用价值。还将利用β-发夹系统来研究碳水化合物-pi相互作用，这是一种通常在碳水化合物结合蛋白中发现的知之甚少的分子识别基序。我们将这些研究的结果与阳离子-π，π-π和疏水相互作用的结果进行比较，以确定这种类型的相互作用的基本方面。然后，我们将其应用于开发碳水化合物受体作为碳水化合物结合蛋白的模拟物。这些研究将提供重要的见解， 碳水化合物的蛋白质结合，这是生物分子识别的一个重要方面。

Molecular design is a powerful tool for assessing our knowledge of molecular recognition events and noncovalent interactions. Our current knowledge of molecular recognition has been advanced greatly through the design of molecular receptors, from early work on crown ethers to current work on receptors for anions. Much has been learned about the complex aspects of protein folding and structure through the de novo design of proteins as well. Conceptually, protein de novo design is also a powerful method for defining critical elements in biomolecular recognition. In this proposal we aim to utilize a designed structured peptide to investigate aspects of biomolecular recognition, including protein-nucleic acid and protein-carbohydrate recognition. We have developed a beta-hairpin peptide that binds to nucleotides and ssDNA through a combination of aromatic stacking and electrostatic interactions. We intend to utilize this system to investigate aspects of sequence and structure-selective recognition of DNA. With regard to structure selective recognition, we will investigate the role of stacking interactions in selective recognition of alkylated bases in duplex DNA, mimicking glycosylase enzymes and mRNA-cap binding proteins. These studies have potential applications to chemotherapy, control of gene expression, and antiviral therapies. A beta-hairpin system will also be utilized to study the carbohydrate-pi interaction, which is a poorly understood molecular recognition motif that is commonly found in carbohydrate binding proteins. We will compare the findings of these studies to those of cation-pi, pi-pi, and hydrophobic interactions to determine fundamental aspects of this type of interaction. We will then apply it to the development of carbohydrate receptors as mimics of carbohydrate-binding proteins. These studies will provide important insights into protein binding of carbohydrates, which is a crucial aspect of biomolecular recognition.