Altering the Electrostatic Potential in the Major Groove: Thermodynamic and Structural Characterization of 7-Deaza-2′-deoxyadenosine:dT Base Pairing in DNA

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.

The toxic effects of mobile phone radiofrequency (940 MHz) on the structure of calf thymus DNA

“…5, the CD spectrum of unexposed ct DNA exhibits a positive elipticity at 275 nm owing to base stacking and a negative elipticity at 245 nm due to right-handed helicity, in agreement with the characteristic B conformation of DNA (Kypr et al, 2009). Compared with the CD spectra of unexposed DNA, the positive cotton effect (Kowal et al, 2011) of the DNA samples immediately after exposure and 2 h after exposure have a blue shift about 9 nm, while the negative cotton effect has no shift in the band positions. In other words, the negative bands corresponding to unwound state of DNA demonstrated a significant reduction for exposed DNA, i.e.…”

Silver Ions in Non‐canonical DNA Base Pairs: Metal‐Mediated Mismatch Stabilization of 2′‐Deoxyadenosine and 7‐Deazapurine Derivatives with 2′‐Deoxycytidine and 2′‐Deoxyguanosine

“…[16] Stable, protonated noncanonical base pairs are assumed to promote the replacement of H + with Ag I ions. [17,18] The 7-deazapurine system changest he pK a of the "adenine" base and enforces base pairing to the Watson-Crick face of the nucleoside, whereas the 7-iodo or 7-cyclopropylr esiduesa re expected to alter the steric demand of silver-mediated base pairs within the major groove of the DNA double helix. Moreover,t he high stability of the non-canonical base pairs used in this study is expected to limit as tabilityi ncrease that is promoted by the incorporation of silver ions compared with the silver-free dCÀdC or dTÀdT mismatched base pairs.…”

Thermodynamic Signature of DNA Damage: Characterization of DNA with a 5-Hydroxy-2′-deoxycytidine·2′-Deoxyguanosine Base Pair

“…The pattern is the same for DNA with 3-methyl-3-deaza-dA•dT, 58 3-deazadA•dT, 58 7-deaza-dG•dC 59 and 7-deaza-dA•dT 60 base pairs. In all cases we observed reduced stability due to an unfavorable enthalpic change that is not fully compensated for by the increase in the entropy term.…”