The understanding of biomolecular recognition of posttranslationally modified histone proteins is centrally important to the histone code hypothesis. Despite extensive binding and structural studies on the readout of histones, the molecular language by which posttranslational modifications on histone proteins are read remains poorly understood. Here we report physical-organic chemistry studies on the recognition of the positively charged trimethyllysine by the electron-rich aromatic cage containing PHD3 finger of KDM5A. The aromatic character of two tryptophan residues that solely constitute the aromatic cage of KDM5A was fine-tuned by the incorporation of fluorine substituents. Our thermodynamic analyses reveal that the wild-type and fluorinated KDM5A PHD3 fingers associate equally well with trimethyllysine. This work demonstrates that the biomolecular recognition of trimethyllysine by fluorinated aromatic cages is associated with weaker cation–π interactions that are compensated by the energetically more favourable trimethyllysine-mediated release of high-energy water molecules that occupy the aromatic cage.

了解翻译后修饰的组蛋白的生物分子识别对于组蛋白密码假说至关重要。尽管对组蛋白的读出进行了广泛的结合和结构研究，但对读取组蛋白翻译后修饰的分子语言仍然知之甚少。在这里，我们报告了关于通过含有 KDM5A 的 PHD3 指的富电子芳香笼识别带正电荷的三甲基赖氨酸的物理有机化学研究。通过掺入氟取代基对单独构成 KDM5A 芳香笼的两个色氨酸残基的芳香特性进行了微调。我们的热力学分析表明，野生型和氟化的 KDM5A PHD3 指与三甲基赖氨酸的结合同样好。