Altering the electrostatic potential in the major groove

Thermodynamic and structural characterization of 7-deaza-2′-deoxyadenosine:dT base pairing in DNA

Ewa A. Kowal, Manjori Ganguly, Pradeep S. Pallan, Luis A Marky, Barry Gold, Martin Egli, Michael P. Stone

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

As part of an ongoing effort to explore the effect of major groove electrostatics on the thermodynamic stability and structure of DNA, a 7-deaza-2′-deoxyadenosine:dT (7-deaza-dA:dT) base pair in the Dickerson-Drew dodecamer (DDD) was studied. The removal of the electronegative N7 atom on dA and the replacement with an electropositive C-H in the major groove was expected to have a significant effect on major groove electrostatics. The structure of the 7-deaza-dA:dT base pair was determined at 1.1 Å resolution in the presence of Mg2+. The 7-deaza-dA, which is isosteric for dA, had minimal effect on the base pairing geometry and the conformation of the DDD in the crystalline state. There was no major groove cation association with the 7-deaza-dA heterocycle. In solution, circular dichroism showed a positive Cotton effect centered at 280 nm and a negative Cotton effect centered at 250 nm that were characteristic of a right-handed helix in the B-conformation. However, temperature-dependent NMR studies showed increased exchange between the thymine N3 imino proton of the 7-deaza-dA:dT base pair and water, suggesting reduced stacking interactions and an increased rate of base pair opening. This correlated with the observed thermodynamic destabilization of the 7-deaza-dA modified duplex relative to the DDD. A combination of UV melting and differential scanning calorimetry experiments were conducted to evaluate the relative contributions of enthalpy and entropy in the thermodynamic destabilization of the DDD. The most significant contribution arose from an unfavorable enthalpy term, which probably results from less favorable stacking interactions in the modified duplex, which was accompanied by a significant reduction in the release of water and cations from the 7-deaza-dA modified DNA.

Original languageEnglish (US)
Pages (from-to)13925-13934
Number of pages10
JournalJournal of Physical Chemistry B
Volume115
Issue number47
DOIs
StatePublished - Dec 1 2011

Fingerprint

grooves
Cotton
Conformations
Cations
Electrostatics
Enthalpy
DNA
deoxyribonucleic acid
Positive ions
Thermodynamics
electrostatics
thermodynamics
Thymine
Water
Dichroism
cotton
destabilization
Protons
Differential scanning calorimetry
Ion exchange

ASJC Scopus subject areas

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

Cite this

Altering the electrostatic potential in the major groove : Thermodynamic and structural characterization of 7-deaza-2′-deoxyadenosine:dT base pairing in DNA. / Kowal, Ewa A.; Ganguly, Manjori; Pallan, Pradeep S.; Marky, Luis A; Gold, Barry; Egli, Martin; Stone, Michael P.

In: Journal of Physical Chemistry B, Vol. 115, No. 47, 01.12.2011, p. 13925-13934.

Research output: Contribution to journalArticle

Kowal, Ewa A. ; Ganguly, Manjori ; Pallan, Pradeep S. ; Marky, Luis A ; Gold, Barry ; Egli, Martin ; Stone, Michael P. / Altering the electrostatic potential in the major groove : Thermodynamic and structural characterization of 7-deaza-2′-deoxyadenosine:dT base pairing in DNA. In: Journal of Physical Chemistry B. 2011 ; Vol. 115, No. 47. pp. 13925-13934.
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abstract = "As part of an ongoing effort to explore the effect of major groove electrostatics on the thermodynamic stability and structure of DNA, a 7-deaza-2′-deoxyadenosine:dT (7-deaza-dA:dT) base pair in the Dickerson-Drew dodecamer (DDD) was studied. The removal of the electronegative N7 atom on dA and the replacement with an electropositive C-H in the major groove was expected to have a significant effect on major groove electrostatics. The structure of the 7-deaza-dA:dT base pair was determined at 1.1 {\AA} resolution in the presence of Mg2+. The 7-deaza-dA, which is isosteric for dA, had minimal effect on the base pairing geometry and the conformation of the DDD in the crystalline state. There was no major groove cation association with the 7-deaza-dA heterocycle. In solution, circular dichroism showed a positive Cotton effect centered at 280 nm and a negative Cotton effect centered at 250 nm that were characteristic of a right-handed helix in the B-conformation. However, temperature-dependent NMR studies showed increased exchange between the thymine N3 imino proton of the 7-deaza-dA:dT base pair and water, suggesting reduced stacking interactions and an increased rate of base pair opening. This correlated with the observed thermodynamic destabilization of the 7-deaza-dA modified duplex relative to the DDD. A combination of UV melting and differential scanning calorimetry experiments were conducted to evaluate the relative contributions of enthalpy and entropy in the thermodynamic destabilization of the DDD. The most significant contribution arose from an unfavorable enthalpy term, which probably results from less favorable stacking interactions in the modified duplex, which was accompanied by a significant reduction in the release of water and cations from the 7-deaza-dA modified DNA.",
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AU - Gold, Barry

AU - Egli, Martin

AU - Stone, Michael P.

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