College of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, China.
School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221116, China.
Molecules. 2024 Sep 29;29(19):4619. doi: 10.3390/molecules29194619.
Polycyclic aromatic compounds (PACs) exhibit rat aryl hydrocarbon receptor (rAhR) activities, leading to diverse biological or toxic effects. In this study, the key amino residues and molecular interactions that govern the rAhR activity of PACs were investigated using in silico strategies. The homology model of rAhR was first docked with 90 PACs to yield complexes, and the results of the molecular dynamics simulations of 16 typical complexes showed that the binding energies of the complexes range from -7.37 to -26.39 kcal/mol. The major contribution to the molecular interaction comes from van der Waals forces, and Pro295 and Arg316 become the key residues involved in most complexes. Two QSAR models were further developed to predict the rAhR activity of PACs (in terms of log IEQ for PACs without halogen substitutions and log%-TCDD-max for halogenated PACs). Both models have good predictive ability, robustness, and extrapolation ability. Molecular polarizability, electronegativity, size, and nucleophilicity are identified as the important factors affecting the rAhR activity of PACs. The developed models could be employed to predict the rAhR activity of other reactive PACs. This work provides insight into the mechanisms and interactions of the rAhR activity of PACs and assists in the assessment of their fate and risk in organisms.
多环芳烃（PACs）表现出大鼠芳烃受体（rAhR）活性，导致多种生物或毒性效应。在这项研究中，使用计算策略研究了控制 PACs 的 rAhR 活性的关键氨基酸残基和分子相互作用。首先将 rAhR 的同源模型与 90 种 PAC 对接，得到复合物，然后对 16 种典型复合物的分子动力学模拟结果表明，复合物的结合能范围为-7.37 至-26.39 kcal/mol。分子相互作用的主要贡献来自范德华力，脯氨酸 295 和精氨酸 316 成为大多数复合物涉及的关键残基。进一步开发了两个 QSAR 模型来预测 PACs 的 rAhR 活性（对于没有卤素取代的 PACs，以 logIEQ 表示，对于卤代 PACs，以 log%-TCDD-max 表示）。这两个模型都具有良好的预测能力、稳健性和外推能力。分子极化率、电负性、大小和亲核性被确定为影响 PACs 的 rAhR 活性的重要因素。开发的模型可用于预测其他反应性 PACs 的 rAhR 活性。这项工作深入了解了 PACs 的 rAhR 活性的机制和相互作用，并有助于评估它们在生物体中的命运和风险。
