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.
| Stewart, Amanda L; Park, Jessica H; Waters, Marcey L (2011) Redesign of a WW domain peptide for selective recognition of single-stranded DNA. Biochemistry 50:2575-84 |
| Stewart, Amanda L; Waters, Marcey L (2009) Structural effects on ss- and dsDNA recognition by a beta-hairpin peptide. Chembiochem 10:539-44 |
| Cline, Lauren L; Waters, Marcey L (2009) The structure of well-folded beta-hairpin peptides promotes resistance to peptidase degradation. Biopolymers 92:502-7 |
| Cline, Lauren L; Waters, Marcey L (2009) Design of a beta-hairpin peptide-intercalator conjugate for simultaneous recognition of single stranded and double stranded regions of RNA. Org Biomol Chem 7:4622-30 |
| Laughrey, Zachary R; Kiehna, Sarah E; Riemen, Alex J et al. (2008) Carbohydrate-pi interactions: what are they worth? J Am Chem Soc 130:14625-33 |
| Kiehna, Sarah E; Laughrey, Zachary R; Waters, Marcey L (2007) Evaluation of a carbohydrate-pi interaction in a peptide model system. Chem Commun (Camb) :4026-8 |
| Hughes, Robert M; Waters, Marcey L (2006) Model systems for beta-hairpins and beta-sheets. Curr Opin Struct Biol 16:514-24 |
| Barrett, Devin G; Minder, C Michael; Mian, Michelle U et al. (2006) Pressure perturbation calorimetry of helical peptides. Proteins 63:322-6 |
| Cooper, W John; Waters, Marcey L (2005) Molecular recognition with designed peptides and proteins. Curr Opin Chem Biol 9:627-31 |
