Figure 8.

Schematic representation of the flexibility of the DNA and its response to drug binding, derived from PCA analysis of the MD data. In the absence of the drug (top) bending at the TpA steps causes each end of the minor groove to fluctuate independently between wide (W) and medium (M) widths. Conformations in which both halves of the minor groove are at their narrowest (M–M) are optimal for drug binding, although ligand binding can occur to any one of these DNA conformations, with subsequent optimisation of the interaction through induced fit, as follows. Once the complex has formed, the TpA step close to the methoxyphenyl end of the ligand becomes narrow and inflexible (N) in order to maximise interactions with the ligand, while the TpA step closer to the positively charged end of the drug remains flexible, allowing the minor groove width in these lowest energy structures to vary between medium (M) and narrow (N).