Chapter 3: Slow DNA Binding

DNA targeting based on slow binding is often hard to assess experimentally and impossible to predict in silico. This is so because selectivity and binding geometry of equilibrium states are relatively straightforward to determine, whereas the path along which the drug reaches this state, the mechanism of binding and the resulting kinetics are harder to predict. Investigating the kinetics of the binding and dissociation reaction could substantially increase our understanding about the structure and dynamics of DNA itself and can, for cases where the interaction kinetics are slow, reveal intermediate binding sites that might be significant in the action of a drug. An overview of the field of slow DNA binding is given, focusing on cases of threading intercalation, i.e. on ligands that have bulky or polar substituents tethered to a part of the molecule that gets intercalated, requiring this part to be threaded through the DNA-base stack so that the resulting complex has one bulky substituent in each groove. Attention is drawn to the counter-intuitive finding that bigger, more hydrophobic substituents may show faster threading kinetics than smaller, more polar ones. This behaviour is attributed to transition states where a hydrophobic moiety interacts with unstacked DNA bases in the opening of a hole through the nucleic acid stack, thus catalysing threading.