Thermodynamic characterization of DNA with 3-deazaadenine and 3-methyl-3-deazaadenine substitutions: The effect of placing a hydrophobic group in the minor groove of DNA

Manjori Ganguly, Ruo Wen Wang, Luis A Marky, Barry Gold

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

In many high-resolution structures of DNA there are ordered waters associated with the floor of the minor groove and extending outward in several layers. It is thought that this hydration structure, along with cations, reduces the Coulombic repulsion of the interstrand phosphates. In previous studies, the replacement of the 3-N atom of adenine with a C-H to afford 3-deazaadenine was shown to decrease the thermodynamic stability of DNA via a reduction in the enthalpic term. Using spectroscopic and calorimetric methods, we report herein a rigorous examination of the thermodynamics of DNA with 3-deazaadenine modifications, and report for the first time how the presence of a minor groove methyl group, i.e., 3-methyl-3-deazaadeine, affects DNA stability, hydration, and cation binding. The methylation of adenine at the N3-position to yield N3-methyladenine represents an important reaction in the toxicity of many anticancer compounds. This minor groove lesion is unstable and cannot be readily studied in terms of its effect on DNA stability or structure. Our studies show that 3-methyl-3-deazaadenine, an isostere of N3-methyladenine, significantly destabilizes DNA (ΔΔ G > 4 kcal•mol-1) due to a significant drop in the enthalpy (ΔH) term, which is associated with a lower hydration of the duplex relative to the unfolded state.

Original languageEnglish (US)
Pages (from-to)7656-7661
Number of pages6
JournalJournal of Physical Chemistry B
Volume114
Issue number22
DOIs
StatePublished - Jun 10 2010

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grooves
DNA
Substitution reactions
deoxyribonucleic acid
Thermodynamics
substitutes
thermodynamics
Hydration
hydration
adenines
Adenine
Cations
Positive ions
cations
methylation
Methylation
toxicity
lesions
Toxicity
3-deaza-3-methyladenine

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

Thermodynamic characterization of DNA with 3-deazaadenine and 3-methyl-3-deazaadenine substitutions : The effect of placing a hydrophobic group in the minor groove of DNA. / Ganguly, Manjori; Wang, Ruo Wen; Marky, Luis A; Gold, Barry.

In: Journal of Physical Chemistry B, Vol. 114, No. 22, 10.06.2010, p. 7656-7661.

Research output: Contribution to journalArticle

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