Parsing the free energy of anthracycline antibiotic binding to DNA
Parsing the free energy of anthracycline antibiotic binding to DNA
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DOI：
10.1021/bi952812r
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发表时间：
1996-02-20
期刊：
影响因子：
2.9
通讯作者：
Priebe, W
中科院分区：
文献类型：
--
作者：
Chaires, JB;Satyanarayana, S;Priebe, W
测定了8种蒽环类抗生素的DNA结合自由能随NaCl浓度的变化。选择与母体化合物阿霉素或柔红霉素在单一化学取代基上不同的化合物进行研究。盐浓度依赖性的结合常数的测定使我们能够解剖的DNA结合自由能的每个化合物到其组件非静电和静电的贡献。非静电自由能的贡献的比较，使我们能够评估净能量的贡献，特定的功能基团的DNA结合。这些定量数据揭示了一个令人惊讶的巨大和有利的能量贡献（2 kcal mol（-1））的沟结合柔红霉素部分和用于改变其立体化学的大量能量罚分，去除C-9和C-14位羟基（结构研究表明可能参与与DNA的氢键相互作用）的能量成本约为1 kcal mol（-1）。用羟基取代3'-氨基导致结合自由能损失0.7 kcal mol（-1），超过了从抗生素中去除其正电荷所产生的能量损失。本文的结果和分析为蒽环类抗生素之间的结构-DNA亲和力关系提供了严格而详细的描述。结果是普遍感兴趣的理解如何总配体结合自由能之间的取代基分配，将是有用的，在制定规则的合理设计的新型DNA结合剂。
The DNA binding free energy of eight anthracycline antibiotics was determined as a function of NaCl concentration, Compounds were chosen for study that differed from the parent compounds, doxorubicin or daunorubicin, at a single chemical substituent. Determination of the salt concentration dependence of the binding constant allowed us to dissect the DNA binding free energy of each compound into its component nonelectrostatic and polyelectrolyte contributions. Comparison of the nonelectrostatic free energy contribution allowed us to evaluate the net energetic contribution of specific functional groups to DNA binding. These quantitative data revealed a surprisingly large and favorable energetic contribution (2 kcal mol(-1)) of the groove-binding daunosamine moiety and a substantial energetic penalty for alteration of its stereochemistry, The energetic cost of removal of hydroxyl groups at the C-9 and C-14 positions (which structural studies indicate may participate in hydrogen-bonding interactions with the DNA) was approximately 1 kcal mol(-1). Replacement of the 3'-amino group with a hydroxyl group led to a loss of 0.7 kcal mol(-1) in binding free energy, above and beyond the energetic penalty resulting from the removal of its positive charge from the antibiotic. The results and analysis presented here provide a rigorous and detailed description of structure-DNA affinity relationships among anthracycline antibiotics. The results are of general interest in understanding how total ligand binding free energies are partitioned among substituents and will be useful in the formulation of rules for the rational design of novel DNA binding agents.