Wang Guimin, Chen Zhaoqiang, Xu Zhijian, Wang Jinan, Yang Yang, Cai Tingting, Shi Jiye, Zhu Weiliang
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
J Phys Chem B. 2016 Feb 4;120(4):610-20. doi: 10.1021/acs.jpcb.5b08139. Epub 2016 Jan 20.
Halogen bonding is the noncovalent interaction between the positively charged σ-hole of organohalogens and nucleophiles. In reality, both the organohalogen and nucleophile could be deprotonated to form anions, which may lead to the vanishing of the σ-hole and possible repulsion between the two anions. However, our database survey in this study revealed that there are halogen bonding-like interactions between two anions. Quantum mechanics calculations with small model complexes composed of halobenzoates and propiolate indicated that the anion-anion halogen bonding is unstable in vacuum but attractive in solvents. Impressively, the QM optimized halogen bonding distance between the two anions is shorter than that in a neutral system, indicating a possibly stronger halogen bonding interaction, which is verified by the calculated binding energies. Furthermore, natural bond orbital and quantum theory of atoms in molecule analyses also suggested stronger anion-anion halogen bonding than that of the neutral one. Energy decomposition by symmetry adapted perturbation theory revealed that the strong binding might be attributed to large induction energy. The calculations on 4 protein-ligand complexes from PDB by the QM/MM method demonstrated that the anion-anion halogen bonding could contribute to the ligands' binding affinity up to ∼3 kcal/mol. Therefore, anion-anion halogen bonding is stable and applicable in reality.
卤键是有机卤化物带正电荷的σ-空穴与亲核试剂之间的非共价相互作用。实际上，有机卤化物和亲核试剂都可能去质子化形成阴离子，这可能导致σ-空穴消失以及两个阴离子之间可能产生排斥。然而，我们在本研究中的数据库调查显示，两个阴离子之间存在类似卤键的相互作用。用由卤代苯甲酸酯和丙炔酸酯组成的小模型配合物进行的量子力学计算表明，阴离子-阴离子卤键在真空中不稳定，但在溶剂中具有吸引力。令人印象深刻的是，两个阴离子之间经量子力学优化的卤键距离比中性体系中的短，这表明卤键相互作用可能更强，这一点通过计算得到的结合能得到了验证。此外，自然键轨道和分子中原子的量子理论分析也表明，阴离子-阴离子卤键比中性卤键更强。通过对称适配微扰理论进行的能量分解表明，强结合可能归因于较大的诱导能。用QM/MM方法对来自蛋白质数据银行（PDB）的4种蛋白质-配体复合物进行的计算表明，阴离子-阴离子卤键可使配体的结合亲和力增加高达约3千卡/摩尔。因此，阴离子-阴离子卤键是稳定的且在实际中是适用的。
