Intercalation of daunomycin into stacked DNA base pairs. DFT study of an anticancer drug

Arturo Silvestri, Antonino Lauria, Anna Maria Almerico, Giampaolo Barone, Célia Fonseca Guerra, F. Matthias Bickelhaupt, Noemi Gambino

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


We have computationally studied the intercalation of the antitumor drug daunomycin into six stacks of Watson-Crick DNA base pairs (i.e., AT-AT, AT-TA, GC-AT, CG-TA, GC-GC, GC-CG) using density functional theory (DFT). The proton affinity of the DNA intercalator daunomycin in water was computed to be 159.2 kcal/mol at BP86/TZ2P, which is in line with the experimental observation that daunomycin is protonated under physiological conditions. The intercalation interaction of protonated daunomycin with two stacked DNA base pairs was studied through a hybrid approach in which intercalation is treated at LDA/TZP while the molecular structure of daunomycin and hydrogen-bonded Watson-Crick pairs is computed at BP86/TZ2P. We find that the affinity of the drug for the six considered base pair dimers decreases in the order AT-AT > AT-TA > GC-AT > GC-TA > GC-CG > GC-GC, in excellent agreement with experimental data on the thermodynamics of the interaction between daunomycin and synthetic polynucleotides in aqueous solution. Our analyses show that the overall stability of the intercalation complexes comes mainly from π?π stacking but an important contribution to the computed and experimentally observed sequence specificity comes from hydrogen bonding between daunomycin and hetero atoms in the minor groove of AT base pairs.
Original languageEnglish
Pages (from-to)115-129
Number of pages15
Publication statusPublished - 2008

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology


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