Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.
Acc Chem Res. 2013 Apr 16;46(4):885-93. doi: 10.1021/ar300265y. Epub 2012 Dec 7.
The chemistry community now recognizes the cation-π interaction as a major force for molecular recognition, joining the hydrophobic effect, the hydrogen bond, and the ion pair in determining macromolecular structure and drug-receptor interactions. This Account provides the author's perspective on the intellectual origins and fundamental nature of the cation-π interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forego aqueous solvation to enter a hydrophobic cavity if that cavity was lined with π systems. Important gas phase studies established the fundamental nature of the cation-π interaction. The strength of the cation-π interaction (Li(+) binds to benzene with 38 kcal/mol of binding energy; NH4(+) with 19 kcal/mol) distinguishes it from the weaker polar-π interactions observed in the benzene dimer or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-π interaction in gas phase studies, the cation-π interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-π interactions can enhance binding energies by 2-5 kcal/mol, making them competitive with hydrogen bonds and ion pairs in drug-receptor and protein-protein interactions. As with other noncovalent interactions involving aromatic systems, the cation-π interaction includes a substantial electrostatic component. The six (four) C(δ-)-H(δ+) bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the π system. Simple electrostatics facilitate a natural attraction of cations to the surface. The trend for (gas phase) binding energies is Li(+) > Na(+) > K(+) > Rb(+): as the ion gets larger the charge is dispersed over a larger sphere and binding interactions weaken, a classical electrostatic effect. On other hand, polarizability does not define these interactions. Cyclohexane is more polarizable than benzene but a decidedly poorer cation binder. Many studies have documented cation-π interactions in protein structures, where lysine or arginine side chains interact with phenylalanine, tyrosine, or tryptophan. In addition, countless studies have established the importance of the cation-π interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-π interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-π interactions. A cation-π interaction plays a critical role in the binding of nicotine to ACh receptors in the brain, an especially significant case. Other researchers have established important cation-π interactions in the recognition of the "histone code," in terpene biosynthesis, in chemical catalysis, and in many other systems.
化学界现在认识到，阳离子-π 相互作用是分子识别的主要作用力之一，与疏水作用、氢键和离子对一起决定了生物大分子的结构和药物受体的相互作用。本综述从作者的视角阐述了阳离子-π 相互作用的理论起源和基本特性。早期对环芳烃的研究表明，如果环芳烃的空腔被π 体系所包围，那么水溶性的、阳离子性的分子将放弃水合溶剂化作用而进入疏水性空腔。重要的气相研究确定了阳离子-π 相互作用的基本特性。阳离子-π 相互作用的强度（Li(+)与苯的结合能为 38 kcal/mol；NH4(+)为 19 kcal/mol）将其与苯二聚体或水-苯复合物中观察到的较弱的极性-π 相互作用区分开来。除了气相研究中阳离子-π 相互作用的固有强度外，在水相介质中和生物条件下，阳离子-π 相互作用仍然具有显著的能量意义。许多研究表明，阳离子-π 相互作用可以增强 2-5 kcal/mol 的结合能，使其在药物受体和蛋白质-蛋白质相互作用中与氢键和离子对具有竞争力。与涉及芳环体系的其他非共价相互作用一样，阳离子-π 相互作用包括相当大的静电成分。苯（乙烯）等分子的六个（四个）C(δ-)-H(δ+)键偶极子结合在一起，在π 体系的表面产生一个负静电势能区域。简单的静电作用促进阳离子自然地被吸引到表面。（气相）结合能的趋势是 Li(+) > Na(+) > K(+) > Rb(+)：随着离子变大，电荷分散在更大的球体上，结合相互作用减弱，这是一种典型的静电效应。另一方面，极化率并不能定义这些相互作用。环己烷的极化率比苯高，但作为阳离子配体的能力却差得多。许多研究已经在蛋白质结构中记录了阳离子-π 相互作用，其中赖氨酸或精氨酸侧链与苯丙氨酸、酪氨酸或色氨酸相互作用。此外，无数研究已经确定了阳离子-π 相互作用在一系列生物过程中的重要性。我们的工作重点是分子神经生物学，我们已经表明，神经递质通常使用阳离子-π 相互作用来与它们的受体结合。我们还表明，许多药物受体的相互作用涉及阳离子-π 相互作用。阳离子-π 相互作用在尼古丁与大脑中的 ACh 受体结合中起着关键作用，这是一个特别重要的例子。其他研究人员已经在识别“组蛋白密码”、萜类生物合成、化学催化以及许多其他系统中建立了重要的阳离子-π 相互作用。
