Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 21, Pages 10506-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv826
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Funding
- Singapore Ministry of Education Academic Research Fund Tier 3 [MOE2012-T3-1-001]
- Nanyang Technological University
- Singapore Ministry of Education Academic Research Fund Tier 2 [MOE2012-T2-1-102]
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G-quadruplexes are four-stranded structures built from stacked G-tetrads (G.G.G.G), which are planar cyclical assemblies of four guanine bases interacting through Hoogsteen hydrogen bonds. A G-quadruplex containing a single guanine analog substitution, such as 8-oxoguanine (O) or xanthine (X), would suffer from a loss of a Hoogsteen hydrogen bond within a G-tetrad and/or potential steric hindrance. We show that a proper arrangement of O and X bases can reestablish the hydrogen-bond pattern within a G.G.X.O tetrad. Rational incorporation of G.G.X.O tetrads in a (3+1) G-quadruplex demonstrated a similar folding topology and thermal stability to that of the unmodified G-quadruplex. pH titration conducted on X.O-modified G-quadruplexes indicated a protonation-deprotonation equilibrium of X with a pKa similar to 6.7. The solution structure of a G-quadruplex containing a G.G.X.O tetrad was determined, displaying the same folding topology in both the protonated and deprotonated states. A G-quadruplex containing a deprotonated X.O pair was shown to exhibit a more electronegative groove compared to that of the unmodified one. These differences are likely to manifest in the electronic properties of G-quadruplexes and may have important implications for drug targeting and DNA-protein interactions.
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