Dissecting the free energy of drug binding to DNA

Advances in polyelectrolyte theory have provided a simple and straightforward basis for dissecting the free energy of ligand binding to DNA into its polyelectrolyte and non-electrostatic contributions. Experimental determination of the ligand-DNA binding constant as a function of monovalent salt concentration is required to provide the quantity (delta lnK(obs)/delta ln[MX]), from which delta Gpe may be calculated. delta Gpe is the contribution to the observed binding free energy from the polyelectrolyte effect. delta Gpe is entropic in origin, and results from the release of DNA-bound cations upon ligand binding. The non-electrostatic free energy contribution, delta Gt, is independent of salt concentration, and reflects the contribution of hydrogen bonding and hydrophobic and van der Waals interactions to the stability of the ligand-DNA complex. When comparing the affinity of different ligands for DNA, it is delta Gt that should be compared, since the effect of ligand charge may then be removed from consideration.