Platination of the (T2G4)4Telomeric Sequence: A Structural and Cross-Linking Study

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Abstract
The telomeric sequence (T2G4)4 was platinated in aqueous solutions containing 50 mM LiClO4, NaClO4, or KClO4. The identification of the guanines which reacted with [Pt(NH3)3(H2O)]2+ revealed that the same type of folding exists in the presence of the three cations and that the latter determine the relative stabilities of the G-quadruplex structures in the order K+ > Na+ ≫ Li+. The tri-ammine complex yielded ca. 40−90% of adducts, mono- and poly-platinated, bound to 4 guanines out of the 16 guanines in the sequence, in the decreasing amounts G9 > G15 ≫ G3 > G21. The formation of these adducts was interpreted with a G-quadruplex structure obtained by restrained molecular dynamics (rMD) simulations which confirms the schematic model proposed by Williamson et al. [(1989) Cell59, 871−880]. The bifunctional complexes cis- and trans-[Pt(NH3)2(H2O)2]2+ also first reacted with G9 and G15 and gave cross-linked adducts between two guanines, which did not exceed 5% each of the products formed. Both the cis and trans isomers formed a G3-G15 platinum chelate, and the second also formed bis-chelates at both ends of the G-quadruplex structure: G3-G15/G9-G21 and G3-G15/G9-G24. The rMD simulations showed that the cross-linking reactions by the trans complex can occur without disturbing the stacking of the three G-quartets.