Dataset Information

Positional effects of click cyclization on ?-hairpin structure, stability, and function.

ABSTRACT: The use of the copper(I)-assisted azide-alkyne cycloaddition (CuAAC, or "click" reaction) as a method of ?-hairpin stabilization was investigated at several different positions to determine the impact on hairpin structure and function, including hydrogen bonded sites, non-hydrogen bonded sites, and at the peptide termini. The role of the turn sequence in the peptide and the chain length of the azide were also investigated. It was determined that the CuAAC reaction was a suitable method for locking in ?-hairpin structure in peptides possessing either the type I' turn, VNGO and the type II' turn, VpGO. Moreover, all cyclic variants exhibited improved thermal stability and resistance to proteolysis as compared to the non-cyclic peptides, regardless of the position in the strand. Additionally, the function of the CuAAC cyclized peptides was not altered as exhibited by similar binding affinities for ATP as the WKWK peptide. These studies provide a comprehensive investigation of CuAAC cyclization of ?-hairpin peptides, which could further be applied to the inhibition of protein-protein and protein-nucleic acid interactions.

SUBMITTER: Park JH

PROVIDER: S-EPMC4037565 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Positional effects of click cyclization on β-hairpin structure, stability, and function.

Park Jessica H JH Waters Marcey L ML

Organic & biomolecular chemistry 20130101 1

The use of the copper(I)-assisted azide-alkyne cycloaddition (CuAAC, or "click" reaction) as a method of β-hairpin stabilization was investigated at several different positions to determine the impact on hairpin structure and function, including hydrogen bonded sites, non-hydrogen bonded sites, and at the peptide termini. The role of the turn sequence in the peptide and the chain length of the azide were also investigated. It was determined that the CuAAC reaction was a suitable method for locki ...[more]

PMID: 23064223

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Project description:Many naturally occurring RNA structures contain single mismatches, many of which occur near the ends of helices. However, previous thermodynamic studies have focused their efforts on thermodynamically characterizing centrally placed single mismatches. Additionally, algorithms currently used to predict secondary structure from sequence are based on two assumptions for predicting the stability of RNA duplexes containing this motif. It has been assumed that the thermodynamic contribution of small RNA motifs is independent of both its position in the duplex and the identity of the non-nearest neighbors. Thermodynamically characterizing single mismatches three nucleotides from both the 3' and 5' ends (i.e., off-center) of an RNA duplex and comparing these results to those of the same single mismatch-nearest neighbor combination centrally located have allowed for the investigation of these effects. The thermodynamic contributions of 13 single mismatch-nearest neighbor combinations are reported, but only nine combinations are studied at all three duplex positions and are used to determine trends and patterns. In general, the 5'- and 3'-shifted single mismatches are relatively similar, on average, and more favorable in free energy than centrally placed single mismatches. However, close examination and comparison shows there are several associated idiosyncrasies with these identified general trends. These peculiarities may be due, in part, to the identities of the single mismatch, the nearest neighbors, and the non-nearest neighbors, along with the effects of the single mismatch position in the duplex. The prediction algorithm recently proposed by Davis and Znosko [Davis, A. R., and Znosko, B. M. (2008) Biochemistry 47, 10178-10187] is used to predict the thermodynamic parameters of single mismatch contribution, and those values are compared to the measured values presented here. This comparison suggests the proposed model is a good approximation but could be improved by the addition of parameters that account for positional and/or non-nearest neighbor effects. However, more data are required to improve our understanding of these effects and to accurately account for them.

Dataset Information

Positional effects of click cyclization on ?-hairpin structure, stability, and function.

Publications

Positional effects of click cyclization on β-hairpin structure, stability, and function.

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