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The Recognition of Nucleotides with Μodel β-Hairpin Receptors:  Investigation of Critical Contacts and Nucleotide Selectivity

We have investigated the factors that contribute to binding of ATP by a designed 12-residue β-hairpin peptide, WKWK, and have determined its selectivity for binding to the naturally occurring nucleotide triphosphates. We have previously shown that WKWK creates an ATP binding pocket on one face of th...

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Bibliographic Details
Published in:Journal of organic chemistry 2005-02, Vol.70 (4), p.1105-1114
Main Authors: Butterfield, Sara M, Sweeney, Michelle M, Waters, Marcey L
Format: Article
Language:English
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Summary:We have investigated the factors that contribute to binding of ATP by a designed 12-residue β-hairpin peptide, WKWK, and have determined its selectivity for binding to the naturally occurring nucleotide triphosphates. We have previously shown that WKWK creates an ATP binding pocket on one face of the β-hairpin consisting of two Trp and two Lys residues. Mutation of the two Lys residues on the binding face of the β-hairpin resulted in a lower affinity, indicating that each is involved in ATP binding and that each residue contributes approximately −1.5 kcal/mol to the energy of complexation. Replacement of either Trp residue of the ATP binding pocket with Phe or Leu destabilizes the complex formed with ATP by approximately 1 kcal/mol, indicating that both Trp residues participate in interactions with ATP. For binding to the nucleotide triphosphates, the order of binding affinity was shown to follow dTTP > GTP > ATP > CTP, with differences in binding energies spanning as much as 1.6 kcal/mol. NMR analysis demonstrates that both aromatic interactions with the Trp side chains and CH−π interactions between the ribose protons and the Trp residues may contribute significantly to binding. The results from our model system provide useful thermodynamic information regarding protein−nucleic acid interactions that occur at the surface of a β-sheet.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo0491105