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-à-vis an efficient nonlinear PBE method. For moderate salt concentrations, the negative derivative, SKpred, of the electrostatic binding free energy, ΔGel, 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 SKpred 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 SKpred, whereas the nonlinear PBE closely matches the experimental results. The PBE predictions of SKpred were not correlated with ΔGel 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 ΔGel 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 SKpred, at least for the charged ligand-nucleic acid complexes studied here, accurate estimates of ΔGel will require further development in theoretical and experimental approaches.
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机译：正确建模非特异性盐介导的静电相互作用对于理解带电配体与核酸的结合至关重要。因为线性Poisson-Boltzmann方程（PBE）和更近似的广义Born方法通常应用于核酸及其与带电配体的相互作用，所以相对于有效的非线性PBE方法，我们检验了这些方法的可靠性。对于中等盐浓度，对于33个阳离子小沟，静电结合自由能ΔGel相对于1：1盐浓度的对数[M + ]的负导数SKpred在所考虑的盐范围（0.1–0.4 M NaCl）中，与AT富集的DNA序列结合的药物被证明始终是阴性的，并且几乎是恒定的。正如抗衡离子缩合理论（CCT）所预测并在热力学结合研究中所观察到的，SKpred的大小近似等于药物上的电荷。线性PBE被证明高估了SKpred的大小，而非线性PBE则与实验结果非常吻合。正如CCT所预期的，在存在介电不连续性的情况下，SKpred的PBE预测与ΔGel不相关。因为这种相关性不成立，所以无法根据报告的实验数据对ΔGel的PBE预测进行参数设置。此外，此处提出的结果对基于实验SK值与基于CCT的静电结合自由能之间的简单关系来提取对带电配体与生物聚电解质结合的静电和非静电贡献的通用实践提出了质疑。尽管刚性对接非线性PB计算可提供对SKpred的可靠预测，但至少对于此处研究的带电配体-核酸配合物而言，对ΔGel的准确估计尚需在理论和实验方法上进一步发展。
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