9.6.2.1 Structure. The first X-ray crystal structure of a monointercalator–DNA complex was obtained by
Wang and Rich in 1987 for the complex between daunomycin and the hexamer d(CGTACG) 2 (Figure 9.6).
Unlike other X-ray structures of simple intercalators bound to dinucleotides, daunomycin binds to DNA with
its long axis almost perpendicular to the long axis of adjacent base pairs. The daunomycin amino sugar,
which is attached to ring A of the anthracycline ring system (Figure 9.4), lies in the minor groove, while ring
D, which contains a methoxy group, protrudes into the major groove. The other two anthracycline rings (B
and C) lie between base pairs. Two bound daunomycin molecules intercalate, one at each of the C G binding
sites at the ends of the duplex. The C G intercalation sites are separated by 3.4 Å and the cationic
amino–sugar substituents, as well as ring A, largely fill the minor groove. In so doing, bound water and ions
are expelled giving rise to a favourable entropic driving force for intercalation. The hydroxyl group on ring
A donates a hydrogen bond to N-3 of guanine and it is a hydrogen-bond acceptor for the amino group of the
same guanine. This gives rise to a favourable enthalpic contribution to binding as well as base pair and orien-
tation specificity for the intercalated drug. The conformations of ring A and of the amino sugar are altered
relative to the unbound drug to facilitate a tight fit of daunomycin into the right-handed minor groove.
The conformation of the drug-bound duplex DNA is also significantly altered relative to free DNA. In
addition to the normal increased separation of base pairs at the intercalation site, the G C base pairs are
also shifted laterally towards the major groove, so that the helix axis changes position. There is no unwind-
ing at the intercalation site itself and the base pairs here maintain a helical twist of 36°, but the base pairs
at adjacent sites are unwound by 8°. Such relatively long-range induced conformational changes provide a
graphic illustration of the flexibility of DNAand demonstrate the significant variations that can occur in
duplex conformation in order to accommodate large and complex intercalators.
Reversible Small Molecule–Nucleic Acid Interactions 351
Figure 9.6 The structure of the daunomycin–DNA complex, (NDB: DDF001, PDB: 1D11). The two intercalated drug
molecules are shown in space fill