With rapid advances in genomics, the next major undertaking is to determine the structure and function of the proteins encoded by newly discovered genes. However, current predictive ability for protein structure is limited, in part because the factors that define a single low energy fold are not yet well understood. Protein de novo design has demonstrated that simple binary coding of hydrophobic and hydrophilic residues is too simplistic a model to define a native-like structure. To gain insight into the factors that contribute to specificity in protein folding, we are investigating the ability of interactions of polarized C-H groups with aromatic rings to provide specificity to protein structure through weakly polar """"""""hydrophobic"""""""" interactions. In proteins, this type of interaction includes, for example, edge-face interactions between two aromatic sidechains, the interaction of a lysine sidechain with an aromatic group, and the interaction of the axial hydrogens of carbohydrates with the x-cloud of an aromatic ring in carbohydrate binding proteins. We expect that these C-H...( interactions would provide stability and specificity to protein structure because the interaction consists of an electrostatic interaction between the electron-poor C-H and the x-cloud of the aromatic ring, in addition to hydrophobic and van der Waals components. We will investigate the nature of these interactions in model B-hairpin peptides and determine their impact on specificity of strand register in B-hairpins. Subsequently, we will determine their effect on folding of the protein ubiquitin, which has been shown to fold via the nucleation of a B-hairpin.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071589-02
Application #
6930647
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Basavappa, Ravi
Project Start
2004-08-01
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
2
Fiscal Year
2005
Total Cost
$215,057
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Riemen, Alexander J; Waters, Marcey L (2009) Design of highly stabilized beta-hairpin peptides through cation-pi interactions of lysine and n-methyllysine with an aromatic pocket. Biochemistry 48:1525-31
Riemen, Alexander J; Waters, Marcey L (2009) Controlling peptide folding with repulsive interactions between phosphorylated amino acids and tryptophan. J Am Chem Soc 131:14081-7
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
Riemen, Alex J; Waters, Marcey L (2008) Stabilization of the N-terminal beta-hairpin of ubiquitin by a terminal hydrophobic cluster. Biopolymers 90:394-8
Hughes, Robert M; Benshoff, Matthew L; Waters, Marcey L (2007) Effects of chain length and N-methylation on a cation-pi interaction in a beta-hairpin peptide. Chemistry 13:5753-64
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; Wiggins, Kimberly R; Khorasanizadeh, Sepideh et al. (2007) Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect. Proc Natl Acad Sci U S A 104:11184-8
Kool, Eric T; Waters, Marcey L (2007) The model student: what chemical model systems can teach us about biology. Nat Chem Biol 3:70-3
Hughes, Robert M; Waters, Marcey L (2006) Model systems for beta-hairpins and beta-sheets. Curr Opin Struct Biol 16:514-24
Hughes, Robert M; Waters, Marcey L (2006) Effects of lysine acetylation in a beta-hairpin peptide: comparison of an amide-pi and a cation-pi interaction. J Am Chem Soc 128:13586-91

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