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知识的有力工具。从早期对冠醚的研究到目前对阴离子受体的研究，我们目前对分子识别的认识已经通过分子受体的设计得到了很大的发展。通过蛋白质的从头设计，人们已经了解了蛋白质折叠和结构的复杂方面。从概念上讲，蛋白质从头设计也是生物分子识别中定义关键元素的有力方法。在这个提议中，我们的目标是利用设计的结构肽来研究生物分子识别的各个方面，包括蛋白质-核酸和蛋白质-碳水化合物

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.