基于分子对接技术预测全氟化合物与胎盘转运蛋白的相互作用

蔡丹; 张艺; 谭素芹

doi:10.11836/JEOM24503

基于分子对接技术预测全氟化合物与胎盘转运蛋白的相互作用

Predicting interactions between perfluoroalkyl substances and placental transporters base on molecular docking

摘要

摘要:
背景胎盘转运蛋白与全氟化合物（PFAS）的亲和力能够影响PFAS的胎盘转运和毒性，但目前PFAS与相关胎盘转运蛋白的相互作用研究有限。
目的基于分子对接技术，探讨PFAS与胎盘转运蛋白的相互作用，为PFAS的毒性预测和胎儿健康风险评估提供理论依据。
方法选取15种PFAS（经三维构化和能量优化）与16种胎盘转运蛋白（三维结构），导入分子对接软件（MOE 20140901）；PFAS设置30种不同构象，在胎盘转运蛋白的活性口袋，采用半柔性对接模式进行对接；以两者的结合能（ΔG，单位为kcal·mol⁻¹）为主要评分指标，结合氢键、配体结合位点的均方根偏差（RMSD）进行排序，输出20种最优对接构象；并选取结合自由能较低（ΔG，范围−3至−10 kcal·mol⁻¹）、氢键作用明确且RMSD≤2.0 Å的结果作为最优对接构型，评估PFAS与胎盘转运蛋白的结合能力。
结果 PFAS能够与胎盘转运蛋白结合，但有一定的结构特异性。如随着PFAS碳链长度的增加，结合能力呈现增加趋势，且PFOS替代品高于传统PFOS；同一碳链长度的磺酸类PFAS的结合能力也强于羧酸类PFAS，如PFOS（C8）与15种胎盘转运蛋白的结合能力均高于PFOA（C8），除了葡萄糖转运体1（PFOS vs. PFOA: −4.14 vs. −4.14）。进一步研究发现，PFAS主要通过氢键、离子键以及疏水作用与胎盘转运蛋白结合。
结论 PFAS能够与胎盘转运蛋白结合，其毒性和暴露风险不容忽视。

Abstract:
Background The affinity between placental transporters and perfluoroalkyl substances (PFAS) could affect the placental transport and toxicity of PFAS, while the study on the interaction between PFAS and placental transporters is limited.
Objective To explore interactions between PFAS and placental transporters using molecular docking, and to provide a theoretical basis for PFAS toxicity prediction and fetal health risk assessment.
Methods Fifteen PFAS compounds, each conformationally sampled and energy-minimized, and 16 placental transporters, represented by their 3D structures, were imported into a molecular docking software (MOE 20140901). For each PFAS, 30 distinct conformations were generated and docked into the active pockets of the transporters using a semi-flexible docking mode. Docking poses were primarily scored and ranked based on their calculated binding free energy (ΔG, kcal·mol⁻¹), with additional consideration given to hydrogen bonding interactions and the ligand's root mean square deviation (RMSD) at the binding site; the top 20 poses for each complex were subsequently output. Optimal binding configurations were identified as those exhibiting a relatively low binding free energy (ΔG ranging from −3 to −10 kcal·mol⁻¹), well-defined hydrogen bonds, and an RMSD ≤ 2.0 Å. The binding capabilities of the PFAS to the placental transporters were then evaluated based on these optimal docking results.
Results The PFAS could bind to the placental transporters, with structural specificity. For example, the binding capabilities increased as the carbon chain length of PFAS increased, and it was also higher for PFOS alternatives than for PFOS. Besides, the binding capabilities of sulfonic PFAS with the same carbon chain length was also stronger than that of carboxylic PFAS. For example, the binding capabilities of PFOS (C8) to 15 placental transporters was higher than that of PFOA (C8), except for glucose transporter 1 (PFOS vs. PFOA: −4.14 vs. −4.14). Further, PFAS might be bound to the placental transporter through hydrogen, ionic, and hydrophobic interactions.
Conclusion PFAS are able to bind the placental transporters, and its toxicity and exposure risk can’t be ignored.

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