Changes in C-13 NMR chemical shifts of DNA as a tool for monitoring drug interactions

\The antibiotic drug, netropsin, was complexed with the DNA oligonucleotide duplex [d(GGTATACC)](2) to explore the effects of ligand binding on the C- 13 NMR chemical shifts of the DNA base and sugar carbons. The binding me de of netrospin to TA-rich tracts of DNA has been well documented and served as an attractive model system. For the base carbons, four large changes in resonance chemical shifts were observed upon complex formation: -0.64ppm fo r carbon 4 of either Ado4 or Ado6, 1.36 ppm for carbon 2 of Thd5, 1.33 ppm for carbon 5 of Thd5 and 0.94 for carbon 6 of Thd5, AdoC4 is covalently bon ded to a heteroatom that is hydrogen bonded to netropsin; this relatively l arge deshielding is consistent with the known hydrogen bond formed at AdoN3 . The three large shielding increases are consistent with hydrogen bonds to water in the minor groove being disrupted upon netropsin binding. For the DNA sugar resonances, Large changes in chemical shifts were observed upon n etropsin complexation. The 2', 3' and 5' C-13 resonances of Thd3 and Thd5 w ere shielded whereas those of Ado4 and Ado6 were deshielded; the C-13 reson ances of 1' and 4' could not be assigned. These changes are consistent with alteration of the dynamic pseudorotational states occupied by the DNA suga rs. A significant alteration in the pseudorotational states of Ado4 or Adoh must occur as suggested by the large change in chemical shift of -1.65 ppm of the C3' carbon. In conclusion, C-13 NMR may serve as a practical tool f or analyzing structural changes in DNA-ligand complexes. (C) 2001 Elsevier Science B.V. All rights reserved.