Department of Chemistry & Biochemistry , University of Montana , Missoula , Montana 59812 , United States.
Department of Biochemistry & Molecular Biology , Colorado State University , Fort Collins , Colorado 80523 , United States.
Acc Chem Res. 2019 Oct 15;52(10):2870-2880. doi: 10.1021/acs.accounts.9b00189. Epub 2019 Jul 18.
The halogen bond (XB) has become an important tool for molecular design in all areas of chemistry, including crystal and materials engineering and medicinal chemistry. Its similarity to the hydrogen bond (HB) makes the relationship between these interactions complex, at times competing against and other times orthogonal to each other. Recently, our two laboratories have independently reported and characterized a synergistic relationship, in which the XB is enhanced through direct intramolecular HBing to the electron-rich belt of the halogen. In one study, intramolecular HBing from an amine polarizes the iodopyridinium XB donors of a bidentate anion receptor. The resulting HB enhanced XB (or HBeXB) preorganizes and further augments the XB donors. Consequently, the affinity of the receptor for halogen anions was significantly increased. In a parallel study, a -chlorotyrosine was engineered into T4 lysozyme, resulting in a HBeXB that increased the thermal stability and activity of the enzyme at elevated temperatures. The crystal structure showed that the chlorine of the noncanonical amino acid formed a XB to the protein backbone, which augmented the HB of the wild-type enzyme. Calorimetric analysis resulted in an enthalpic contribution of this Cl-XB to the stability of the protein that was an order of magnitude greater than previously determined in biomolecules. Quantum mechanical (QM) calculations showed that rotating the hydroxyl group of the tyrosine to point toward rather than away from the halogen greatly increased its potential to serve as a XB donor, equivalent to what was observed experimentally. In sum, the two systems described here show that the HBeXB concept extends the range of interaction energies and geometries to be significantly greater than that of the XB alone. Additionally, surveys of structural databases indicate that the components for this interaction are already present in many existing molecular systems. The confluence of the independent studies from our two laboratories demonstrates the reach of the HBeXB across both chemistry and biochemistry and that intentional engineering of this enhanced interaction will extend the applications of XBs beyond these two initial examples.
卤键 (XB) 已成为化学各领域（包括晶体和材料工程以及药物化学）分子设计的重要工具。它与氢键 (HB) 的相似性使得这两种相互作用的关系变得复杂，有时相互竞争，有时相互正交。最近，我们两个实验室独立报道并描述了一种协同关系，其中 XB 通过直接分子内 HB 作用于富电子的卤带得到增强。在一项研究中，伯胺的分子内 HB 使双齿阴离子受体的碘吡啶鎓 XB 供体极化。由此产生的 HB 增强 XB（或 HBeXB）使 XB 供体预组织并进一步增强。因此，受体对卤阴离子的亲和力显著增加。在平行研究中，将 - 氯酪氨酸工程改造到 T4 溶菌酶中，形成 HBeXB，提高了酶在高温下的热稳定性和活性。晶体结构表明，非典型氨基酸的氯与蛋白质骨架形成 XB，增强了野生型酶的 HB。量热分析导致该非经典氨基酸的 Cl-XB 对蛋白质稳定性的焓贡献比以前在生物分子中确定的要大一个数量级。量子力学 (QM) 计算表明，将酪氨酸的羟基旋转指向而不是远离卤素，可大大增加其作为 XB 供体的潜力，这与实验观察到的结果相当。总之，这里描述的两个系统表明，HBeXB 概念扩展了相互作用能量和几何形状的范围，使其显著大于单独的 XB。此外，结构数据库的调查表明，这种相互作用的组成部分已经存在于许多现有分子系统中。我们两个实验室的独立研究表明，HBeXB 跨越化学和生物化学两个领域，并且这种增强相互作用的有意设计将使 XB 的应用超越这两个初始示例。
