Andersson C David, Mishra Brijesh Kumar, Forsgren Nina, Ekström Fredrik, Linusson Anna
Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden.
International Institute of Information Technology, Bangalore, Karnataka 560003, India.
J Phys Chem B. 2020 Jul 30;124(30):6529-6539. doi: 10.1021/acs.jpcb.0c03778. Epub 2020 Jul 20.
Arene-arene interactions play important roles in protein-ligand complex formation. Here, we investigate the characteristics of arene-arene interactions between small organic molecules and aromatic amino acids in protein interiors. The study is based on X-ray crystallographic data and quantum mechanical calculations using the enzyme acetylcholinesterase and selected inhibitory ligands as a model system. It is shown that the arene substituents of the inhibitors dictate the strength of the interaction and the geometry of the resulting complexes. Importantly, the calculated interaction energies correlate well with the measured inhibitor potency. Non-hydrogen substituents strengthened all interaction types in the protein milieu, in keeping with results for benzene dimer model systems. The interaction energies were dispersion-dominated, but substituents that induced local dipole moments increased the electrostatic contribution and thus yielded more strongly bound complexes. These findings provide fundamental insights into the physical mechanisms governing arene-arene interactions in the protein milieu and thus into molecular recognition between proteins and small molecules.
芳基-芳基相互作用在蛋白质-配体复合物形成过程中发挥着重要作用。在此，我们研究了蛋白质内部小分子与芳香族氨基酸之间芳基-芳基相互作用的特征。该研究基于X射线晶体学数据以及使用乙酰胆碱酯酶和选定的抑制性配体作为模型系统的量子力学计算。结果表明，抑制剂的芳基取代基决定了相互作用的强度以及所得复合物的几何结构。重要的是，计算得到的相互作用能与测得的抑制剂效力具有良好的相关性。非氢取代基增强了蛋白质环境中所有类型的相互作用，这与苯二聚体模型系统的结果一致。相互作用能以色散为主，但诱导局部偶极矩的取代基增加了静电贡献，从而产生结合更紧密的复合物。这些发现为蛋白质环境中芳基-芳基相互作用的物理机制提供了基本见解，进而为蛋白质与小分子之间的分子识别提供了基本见解。
