title: Xanthine and 8-oxoguanine in G-quadruplexes: formation of a G·G·X·O tetrad.
abstract: 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 ∼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.
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371 Singapore.
authors.forename: Vee Vee
authors.initials: VV
authors.lastname: Cheong
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371 Singapore.
authors.forename: Brahim
authors.initials: B
authors.lastname: Heddi
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371 Singapore.
authors.forename: Christopher Jacques
authors.initials: CJ
authors.lastname: Lech
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University, 637371 Singapore phantuan@ntu.edu.sg.
authors.forename: Anh Tuân
authors.initials: AT
authors.lastname: Phan
mesh_terms: D054856:G-Quadruplexes; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011522:Protons; D016615:Telomere / Q000737:chemistry; D019820:Xanthine / Q000737:chemistry*
chemical_list: D011522:Protons; D019820:Xanthine; C024829:8-hydroxyguanine; D006147:Guanine