Journal
BIOCHIMIE
Volume 165, Issue -, Pages 170-178Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biochi.2019.07.021
Keywords
Antiviral; Thermodynamics; Polyamide; DNA; Stoichiometry; Fluorescence
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Funding
- NSF [1337638]
- American Chemical Society Petroleum Research Fund [53383-ND4]
- Louis College of Arts and Sciences
- Division Of Chemistry
- Direct For Mathematical & Physical Scien [1337638] Funding Source: National Science Foundation
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The interactions of 6-8 ring hairpin polyamides (PAs) with the minor groove of DNA have been investigated extensively. More recent studies of large antiviral PAs (14-20 rings) active against small DNA tumor viruses lead to questions regarding the extent to which the DNA binding behaviors of the well studied, smaller PAs can be reliably extrapolated to the larger ones. Described here is the first reported study of hairpin PA-DNA binding thermodynamics as a function of PA size (6-20 rings). All PAs exhibit binding affinity in the low nM to upper pM range, which indicates that affinity is not a discriminator of antiviral activity. Unlike the smaller PAs, a 20-ring PA does not appreciably dissociate from DNA in competition experiments, which indicates very long residence time that is consistent with antiviral activity. While the DNA binding thermodynamics for the smaller antivirally inactive 6- and 8-ring PAs is clearly enthalpically driven, the larger antiviral PAs (14- and 20-rings) exhibit strongly entropically-driven DNA binding. These distinct energetic signatures indicate that different types of interactions drive these associations. In DNA binding site stoichiometry experiments conducted at both nM and mu M concentrations, all PAs except the 6- ring PA bind an isolated site with site stoichiometry of at least two PAs per recognition sequence. Electrostatic contributions to DNA binding affinity are small for all PAs and not correlated with PA size but weakly correlated with the number of imidazole residues. Altogether, these results indicate that DNA binding behaviors of smaller hairpin PAs do not necessarily reflect those of larger PAs. These are vital considerations in the development of hairpin PAs for biological use. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.
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