Rohs Remo, Sklenar Heinz
Theoretical Biophysics Group, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, 13092 Berlin, Germany.
J Biomol Struct Dyn. 2004 Apr;21(5):699-711. doi: 10.1080/07391102.2004.10506960.
The results presented in this paper on methylene blue (MB) binding to DNA with AT alternating base sequence complement the data obtained in two former modeling studies of MB binding to GC alternating DNA. In the light of the large amount of experimental data for both systems, this theoretical study is focused on a detailed energetic analysis and comparison in order to understand their different behavior. Since experimental high-resolution structures of the complexes are not available, the analysis is based on energy minimized structural models of the complexes in different binding modes. For both sequences, four different intercalation structures and two models for MB binding in the minor and major groove have been proposed. Solvent electrostatic effects were included in the energetic analysis by using electrostatic continuum theory, and the dependence of MB binding on salt concentration was investigated by solving the non-linear Poisson-Boltzmann equation. We find that the relative stability of the different complexes is similar for the two sequences, in agreement with the interpretation of spectroscopic data. Subtle differences, however, are seen in energy decompositions and can be attributed to the change from symmetric 5'-YpR-3' intercalation to minor groove binding with increasing salt concentration, which is experimentally observed for the AT sequence at lower salt concentration than for the GC sequence. According to our results, this difference is due to the significantly lower non-electrostatic energy for the minor groove complex with AT alternating DNA, whereas the slightly lower binding energy to this sequence is caused by a higher deformation energy of DNA. The energetic data are in agreement with the conclusions derived from different spectroscopic studies and can also be structurally interpreted on the basis of the modeled complexes. The simple static modeling technique and the neglect of entropy terms and of non-electrostatic solute-solvent interactions, which are assumed to be nearly constant for the compared complexes of MB with DNA, seem to be justified by the results.
本文展示的关于亚甲蓝（MB）与具有AT交替碱基序列的DNA结合的结果，补充了之前两项关于MB与GC交替DNA结合的建模研究中获得的数据。鉴于这两个系统的大量实验数据，本理论研究聚焦于详细的能量分析和比较，以了解它们不同的行为。由于复合物的实验高分辨率结构不可得，分析基于不同结合模式下复合物的能量最小化结构模型。对于这两种序列，已提出四种不同的嵌入结构以及两种MB在小沟和大沟中结合的模型。通过使用静电连续介质理论将溶剂静电效应纳入能量分析，并通过求解非线性泊松 - 玻尔兹曼方程研究了MB结合对盐浓度的依赖性。我们发现，对于这两种序列，不同复合物的相对稳定性相似，这与光谱数据的解释一致。然而，在能量分解中可以看到细微差异，这可归因于随着盐浓度增加，从对称的5'-YpR-3'嵌入转变为小沟结合，实验观察到AT序列在比GC序列更低的盐浓度下发生这种转变。根据我们的结果，这种差异是由于与AT交替DNA形成的小沟复合物的非静电能量显著更低，而与该序列结合能略低是由DNA更高的变形能引起的。能量数据与不同光谱研究得出的结论一致，并且也可以基于建模的复合物进行结构解释。简单的静态建模技术以及对熵项和非静电溶质 - 溶剂相互作用的忽略（假设对于MB与DNA的比较复合物而言这些相互作用几乎恒定），似乎从结果来看是合理的。
