Revisiting the Association of Cationic Groove-Binding Drugs to DNA Using a Poisson-Boltzmann Approach

Proper modeling of nonspecific salt-mediated electrostatic interactions is essential to understanding the binding of charged ligands to nucleic acids. Because the linear Poisson-Boltzmann equation (PBE) and the more approximate generalized Born approach are applied routinely to nucleic acids and their interactions with charged ligands, the reliability of these methods is examined vis-a-vis an efficient nonlinear PBE method. For moderate salt concentrations, the negative derivative, SK(pred), of the electrostatic binding free energy, Delta G(el), with respect to the logarithm of the 1:1 salt concentration, [M(+)], for 33 cationic minor groove drugs binding to AT-rich DNA sequences is shown to be consistently negative and virtually constant over the salt range considered (0.1-0.4 M NaCl). The magnitude of SK(pred) is approximately equal to the charge on the drug, as predicted by counterion condensation theory (CCT) and observed in thermodynamic binding studies. The linear PBE is shown to overestimate the magnitude of SK(pred), whereas the nonlinear PBE closely matches the experimental results. The PBE predictions of SK(pred) were not correlated with Delta G(el) in the presence of a dielectric discontinuity, as would be expected from the CCT. Because this correlation does not hold, parameterizing the PBE predictions of Delta G(el) against the reported experimental data is not possible. Moreover, the common practice of extracting the electrostatic and nonelectrostatic contributions to the binding of charged ligands to biopolyelectrolytes based on the simple relation between experimental SK values and the electrostatic binding free energy that is based on CCT is called into question by the results presented here. Although the rigid-docking nonlinear PB calculations provide reliable predictions of SK(pred), at least for the charged ligand-nucleic acid complexes studied here, accurate estimates of Delta G(el) will require further development in theoretical and experimental approaches.