Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, T1K 3M4 Canada.
J Phys Chem B. 2009 Dec 10;113(49):16046-58. doi: 10.1021/jp907887y.
Detailed (gas-phase) MP2/6-31G*(0.25) potential energy surface scans and CCSD(T) energy calculations at the complete basis set (CBS) limit were used to analyze the (face-to-face) stacking and (edge-to-face) T-shaped interactions between histidine (modeled as imidazole) and the DNA nucleobases. For the first time, a variety of relative monomer arrangements between both neutral and protonated histidine and the natural nucleobases were considered to determine the effects of charge on the optimum dimer geometry and binding strength. Our results reveal that protonation of histidine changes the preferred relative orientations of the monomers and propose that these geometric differences may be combined with experimental crystal structures to assess the protonation state of histidine in different environments. It is also found that protonation affects the nucleobase binding preference, as well as the magnitude of the stacking and T-shaped interactions. Indeed, the maximum possible stacking and T-shaped interactions involving the neutral histidine range between approximately 20 and 45 kJ mol(-1), while this range increases to 40-105 kJ mol(-1) upon protonation, which represents an up to 330% enhancement. Although an increase in the interaction energies upon protonation of histidine is expected, the present work provides a measure of the magnitude of this enhancement in the gas phase and reveals that the amplification is almost entirely due to larger electrostatic contributions. The relative strengthening of different classifications of dimers upon protonation leads to stronger T-shaped interactions than stacking energies for protonated histidine, while the stacking and T-shaped interactions involving neutral histidine are of comparable magnitude. Thus, there is a significant difference in the nature of the pi(cation)-pi interactions involving protonated histidine and the pi-pi interactions involving neutral histidine. The calculated strengths of the interactions studied in the present work suggest that both neutral and cationic histidine contacts will provide significant stabilization to DNA-protein complexes. Although solvation effects will decrease the magnitude of the reported interactions, our results are applicable to a variety of low-polarity, biologically-relevant environments such as nonpolar enzyme active sites. Therefore, our calculations suggest that these interactions may also be important for many biological processes. The proposed significance of these interactions is supported by the large number of histidine-nucleobase contacts that appear in experimental crystal structures. The highly accurate (MP2/6-31G*(0.25)) preferred structures and (CCSD(T)/CBS) binding strengths reported in the present work can be used as benchmarks to analyze the performance of existing, or to develop new, molecular mechanics force fields for use in large-scale molecular dynamics (MD) studies of DNA-protein complexes.
利用详细的（气相）MP2/6-31G*（0.25）势能面扫描和完全基组（CBS）极限下的 CCSD(T)能量计算，分析了组氨酸（模拟为咪唑）与 DNA 碱基之间的（面对面）堆积和（边缘对面对面）T 型相互作用。首次考虑了中性和质子化组氨酸与天然碱基之间各种相对单体排列，以确定电荷对最佳二聚体几何形状和结合强度的影响。我们的结果表明，组氨酸的质子化改变了单体的优先相对取向，并提出这些几何差异可能与实验晶体结构相结合，以评估不同环境中组氨酸的质子化状态。还发现质子化会影响碱基结合偏好以及堆积和 T 型相互作用的大小。事实上，涉及中性组氨酸的最大可能堆积和 T 型相互作用范围在 20 到 45 kJ mol(-1) 之间，而在质子化时，这个范围增加到 40-105 kJ mol(-1)，增加了 330%。尽管预计组氨酸质子化会增加相互作用能，但本工作提供了在气相中增强幅度的度量，并表明这种增强几乎完全归因于更大的静电贡献。质子化后不同类型二聚体的相对增强导致质子化组氨酸的 T 型相互作用强于堆积能，而涉及中性组氨酸的堆积和 T 型相互作用具有相当的大小。因此，涉及质子化组氨酸的 pi(cation)-pi 相互作用与涉及中性组氨酸的 pi-pi 相互作用在性质上有显著差异。本工作研究的相互作用的计算强度表明，中性和阳离子组氨酸接触将为 DNA-蛋白质复合物提供显著的稳定性。尽管溶剂化效应会降低报告相互作用的幅度，但我们的结果适用于各种低极性、生物相关的环境，如非极性酶活性位点。因此，我们的计算表明，这些相互作用对于许多生物过程也可能很重要。实验晶体结构中出现的大量组氨酸-碱基接触支持了这些相互作用的重要意义。本工作中报告的高度精确的（MP2/6-31G*（0.25））优先结构和（CCSD(T)/CBS）结合强度可用作基准来分析现有分子力学力场的性能，或开发用于大规模 DNA-蛋白质复合物分子动力学（MD）研究的新力场。
