Structural and Dynamic Aspects of Non-Intercalative (1:1) Binding of a Thiazole-Lexitropsin to the Decadeoxyribonucleotide d-[CGCAATTGCG]2: An1H-NMR and Molecular Modeling Study

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Abstract
The location, orientation and dynamics of a thiazole-containing analogue of distamycin 1 bound to the decadeoxyribonucleotide d-[CGCAATTGCG]2 have been studied by non- exchangable and imino proton NMR resonances of the 1:1 complex. Using NOE difference, COSY and NOESY experiments, lexitropsin (1) was located in the minor groove of DNA at 5′-CAAT sequence. This was concluded by an intermolecular NOE between the ligand and a minor groove A4H2 proton. The NOE cross-correlations in the NOESY map confirmed that the DNA decamer duplex in the 1:1 complex remains in a right-handed B-conformation similar to that in the free decamer. Experiments on non-exchangeable and exchangeable proton NMR resonances placed the N-formylamino terminus of drug 1 on the 5′-C3 nucleotide, while the rest of the molecule extends onto the 5′-AAT sequence. The structural evidence for sequence preferential binding at 5′CAAT rather than 5′AATT suggests this reflects an attempt on the part of the sterically demanding inward directed sulfur of the thiazole to minimize compression by moving part of the molecule to the somewhat wider CG base site. The lack of evidence for a 2:1 drug:DNA complex, in contrast to distamycin, is in accord with this interpretation. The lexitropsin 1 was found to be in an exchange between the equivalent 5′-CAAT sites at a rate of ∼35 s−1 with a ΔG° of 65 ±5 kJ mol−1 at 303K. The experimental data suggests a slide-swing mechanism for this exchange process.

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