DNA小沟结合药物DB818的分子动力学模拟和结合自由能分析

Minor Groove Binding between DB818 and DNA: a Molecular Dynamics Simulation and Binding Free Energy Analysis

采用分子动力学模拟了DNA小沟结合芳香二脒药物DB818形成的复合物.通过5ns的模拟研究表明:DB818药物分子可紧密结合在DNA的AATTC小沟区域,和双螺旋d[CGCGAATTCGCG]2形成稳定的复合物.由于噻吩硫原子的弱电负性,使DB818能够以更大的伸展程度与DNA的小沟结合,形成更强的结合力.DB818苯并咪唑的氮原子能够与DNA7位和19位T碱基上的氧原子形成两个稳定的氢键,同时,DB818末端氨基氮原子分别与DNA的20位T碱基的氧原子和9位C碱基的氧原子形成两个氢键.另外,运用MM_PBSA方法计算了DB293-DNA和DB818-DNA复合物的结合自由能,计算结合能与实验值能较好的吻合,通过比较其结合自由能,从热力学能量角度说明了DB818有较大的熵值与较小的焓值贡献,从而与DNA小沟结合的结合力比DB293强.本文在分子水平上提供了DB818直接与双螺旋DNA相互作用的结构及复合物的动态变化情况,为设计出更高生物活性的DNA小沟结合剂提供一定的理论依据.

Molecular dynamics simulations were used to investigate the interaction of DB818 with the DNA oligonucleotide d[CGCGAATTCGCG]2. A 5 ns MD calculation was performed to study the DB818-DNA complex and the results indicated that DB818 was inserted in the minor groove of DNA, binding to the region of duplex AATTC bases. The enhanced binding of DB818 to DNA is primary due to a more favorable curvature contribution and matches well the DNA minor groove topology. The bifurcated pair of H-bonds was formed between nitrogen atom of the benzimidazole ring and oxygen atoms of the thymine 7 and thymine 19, and other two specific H-bonds were formed between nitrogen atom of the amidinium group and oxygen atoms of thymine 20 and cytosine 9. Furthermore, the binding free energy of DB293-DNA and DB818-DNA complexes was calculated with MM_PBSA methods, and all of results were consistent with the literature data. Thermodynamics analysis showed that the enhanced binding of DB818 to AATT was due to much lager entropy and less enthalpy contribution. Molecular dynamics studies complement the structural analysis and offer a clear picture of the complex, providing the theoretical guidance for the design of biologically active minor groove agents.