(9.7)and
(9.8)where ln KTand the corresponding free energy term GTrefer to a standard state of [MX] of 1 M Gpeis
the polyelectrolyte contribution to the overall free energy
(9.9)Gpeis a favourable free energy contribution that arises from the entropically favoured release of
counter-ions into bulk solvent on binding of a cationic ligand. By experimental determination of the value
of lnKobs/ln[MX], Gpecan be calculated at any given salt concentration through use of Equation 9.9. From
experiments and simulations, it is clear that Gpecan be quite large, even at modest salt concentrations,
and it can contribute several kJ to the overall binding free energy. The difference between Gpeand the
experimental Gobs(determined at the same salt concentration) is equal to GT, which is the nonpolyelec-
trolyte contribution to free energy. GTis independent of salt concentration and represents the free energy
arising from all types of interactions other than coupled polyelectrolyte effects, such as van der Waals
interactions, hydrogen bonding, and hydrophobic effects. The use of polyelectrolyte theory to probe the
energetics of drug–DNA interactions has been discussed in a useful review article.^5
9.3.1 Intercalation and Polyelectrolyte Theory
To accommodate an intercalating ligand, the nucleic acid base pairs at the intercalation site must be sep-
arated by an additional 3.4 Å (Section 9.6). This lengthens the helix and increases the inter-phosphate spa-
cing, parameter bin Equation 9.1. It then leads to a decrease in and a decrease in the fraction of
monovalent cations associated per phosphate group. For intercalation, there are two distinct factors that
contribute to the polyelectrolyte effect: (1) release of condensed counter-ions following binding of a posi-
tively charged ligand (as discussed above), and (2) a contribution that arises from increased phosphate spa-
cing that results from intercalation-induced conformational changes in the DNA. For a neutral intercalator, the
observed binding constant is still dependent on salt concentration, since the intercalator induces a structural
transition uponbinding.
David Wilson has described a modification of Record’s theory that accounts for ion release arising from a
DNA structural transition.^6 He predicted values for lnKobs/ln[MX] of 1.06 and 1.89 for the binding of
mono- and dicationic intercalators, respectively. Later Friedman and Manning used the same general concept
but with a different theoretical model to predict values for lnKobs/ln[MX] of 0.24 and 1.24 for the bind-
ing of uncharged and monocationic intercalators, respectively.^7
9.4 Non-specific Outside-Edge Interactions
There are several types of molecule that can interact non-specifically with the nucleic acid phosphate
backbone through mainly electrostatic interactions. The archetypal outside-edge binding drugsare the
polyamines,spermineand spermidine(Figure 9.2).
The nonspecific nature of the interaction between DNA and polyaminesmeans that it is difficult to
obtain high-resolution NMR or crystallographic structural data on these complexes. In fact these ligands
are often used to reduce charge–charge effects in crystallographic studies, since they can rarely be seen at
high-density sites in a resolved structure.
Polyamines such as spermine are ubiquitous in eukaryotic cells and these ligands are thought to play
multiple roles in cellular function. One important role is in DNA packaginginto chromatin, but the exact
GZRTMXpe ln[ ]
GGGobs T pelnKKZMXobs ln T ln[ ]Reversible Small Molecule–Nucleic Acid Interactions 345