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首页> 外文期刊>Biochemistry >Understanding Mixed Sequence DNA Recognition by Novel Designed Compounds: The Kinetic and Thermodynamic Behavior of Azabenzimidazole Diamidines
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Understanding Mixed Sequence DNA Recognition by Novel Designed Compounds: The Kinetic and Thermodynamic Behavior of Azabenzimidazole Diamidines

机译：了解新颖的设计化合物的混合序列DNA识别：氮苯并咪唑二氨基氨基氨酸的动力学和热力学行为

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摘要

Sequence-specific recognition of DNA by small organic molecules offers a potentially effective approach for the external regulation of gene expression and is an important goal in cell biochemistry. Rational design of compounds from established modules can potentially yield compounds that bind strongly and selectively with specific DNA sequences. An initial approach is to start with common A.T bp recognition molecules and build in G.C recognition units. Here we report on the DNA interaction of a synthetic compound that specifically binds to a G.C bp in the minor groove of DNA by using an azabenzimidazole moiety. The detailed interactions were evaluated with biosensor-surface plasmon resonance (SPR), isothermal calorimetric (ITC), and mass spectrometry (ESI-MS) methods. The compound, DB2277, binds with single G.C bp containing sequences with sub-nanomolar potency and displays slow dissociation kinetics and high selectivity. A detailed thermodynamic and kinetic study at different experimental salt concentrations and temperatures shows that the binding free energy is salt concentration dependent but essentially temperature independent under our experimental conditions, and binding enthalpy is temperature dependent but salt concentration independent. The results show that in the proper compound structural context novel heterocyclic cations can be designed to strongly recognize complex DNA sequences.
机译：小型有机分子对DNA的序列特异性识别为基因表达的外部调节提供了潜在有效的方法，并且是细胞生物化学中的重要目标。来自已建立的模块的化合物的理性设计可以潜在地产生具有特定DNA序列的强烈和选择性的化合物。初始方法是以常见的A.T BP识别分子开始，并以G.C识别单元构建。在这里，我们通过使用氮哒咪唑部分将特异性结合到DNA的小槽中的G.C BP的合成化合物的DNA相互作用报告。通过生物传感器表面等离子体共振（SPR），等温量热（ITC）和质谱（ESI-MS）方法评估详细的相互作用。该化合物DB2277与含有亚纳摩效力的单个G.C BP结合，并显示缓慢的解离动力学和高选择性。在不同实验盐浓度和温度下进行详细的热力学和动力学研究表明，结合的自由能量是盐浓度依赖性但在我们的实验条件下独立的温度无关，并且结合焓是温度依赖性但盐浓度无关。结果表明，在适当的复合结构上下文中，可以设计新的杂环阳离子以强烈识别复杂的DNA序列。

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