Per- and Polyfluoroalkyl Substances (PFAS) bioaccumulate in the human body, presenting potential health risks and cellular toxicity. Their transport mechanisms and interactions with tissues and the circulatory system require further investigation. This study investigates the interaction mechanisms of six PFAS with Human Serum Albumin (HSA) using multi-spectroscopy, DFT and a molecular dynamics approach. Multi-spectral analysis shows that perfluorononanoic acid (PFNA) has the best binding capabilities with HSA. The order of binding constants (298 K) is as follows: “Perfluorononanoic Acid (PFNA, 7.81 × 106 L·mol−1) > Perfluoro-2,5-dimethyl-3,6-dioxanonanoic Acid (HFPO-TA, 3.70 × 106 L·mol−1) > Perfluorooctanoic Acid (PFOA, 2.27 × 105 L·mol−1) > Perfluoro-3,6,9-trioxadecanoic Acid (PFO3DA, 1.59 × 105 L·mol−1) > Perfluoroheptanoic Acid (PFHpA, 4.53 × 103 L·mol−1) > Dodecafluorosuberic Acid (DFSA, 1.52 × 103 L·mol−1)”. Thermodynamic analysis suggests that PFNA and PFO3DA’s interactions with HSA are exothermic, driven primarily by hydrogen bonds or van der Waals interactions. PFHpA, DFSA, PFOA, and HFPO-TA’s interactions with HSA, on the other hand, are endothermic processes primarily driven by hydrophobic interactions. Competitive probe results show that the main HSA–PFAS binding site is in the HSA structure’s subdomain IIA. These findings are also consistent with the findings of molecular docking. Molecular dynamics simulation (MD) analysis further shows that the lowest binding energy (−38.83 kcal/mol) is fund in the HSA–PFNA complex, indicating that PFNA binds more readily with HSA. Energy decomposition analysis also indicates that van der Waals and electrostatic interactions are the main forces for the HSA–PFAS complexes. Correlation analysis reveals that DFT quantum chemical descriptors related to electrostatic distribution and characteristics like ESP and ALIE are more representative in characterizing HSA–PFAS binding. This study sheds light on the interactions between HSA and PFAS. It guides health risk assessments and control strategies against PFAS, serving as a critical starting point for further public health research.

中文翻译：

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六种 PFAS 与人血清白蛋白的结合亲和力和机制：来自多光谱、DFT 和分子动力学方法的见解

全氟烷基物质和多氟烷基物质 (PFAS) 在人体内生物累积，带来潜在的健康风险和细胞毒性。它们的运输机制以及与组织和循环系统的相互作用需要进一步研究。本研究利用多光谱、DFT 和分子动力学方法研究了六种 PFAS 与人血清白蛋白 (HSA) 的相互作用机制。多光谱分析表明，全氟壬酸（PFNA）与HSA具有最佳的结合能力。结合常数 (298 K) 的顺序如下：“全氟壬酸 (PFNA, 7.81 × 106 L·mol−1) > 全氟-2,5-二甲基-3,6-二氧杂壬酸 (HFPO-TA, 3.70 × 106 L·mol−1) > 全氟辛酸 (PFOA, 2.27 × 105 L·mol−1) > 全氟 3,6,9-三氧杂癸酸 (PFO3DA, 1.59 × 105 L·mol−1) > 全氟庚酸 (PFHpA) , 4.53 × 103 L·mol−1) > 十二氟辛二酸 (DFSA, 1.52 × 103 L·mol−1)”。热力学分析表明，PFNA 和 PFO3DA 与 HSA 的相互作用是放热的，主要由氢键或范德华相互作用驱动。另一方面，PFHpA、DFSA、PFOA 和 HFPO-TA 与 HSA 的相互作用是主要由疏水相互作用驱动的吸热过程。竞争性探针结果表明，HSA-PFAS 的主要结合位点位于 HSA 结构的子域 IIA 中。这些发现也与分子对接的结果一致。分子动力学模拟（MD）分析进一步表明，HSA-PFNA复合物中的结合能最低（−38.83 kcal/mol），表明PFNA更容易与HSA结合。能量分解分析还表明范德华力和静电相互作用是 HSA-PFAS 复合物的主要作用力。相关分析表明，与静电分布和 ESP 和 ALIE 等特征相关的 DFT 量子化学描述符在表征 HSA-PFAS 结合方面更具代表性。这项研究揭示了 HSA 和 PFAS 之间的相互作用。它指导健康风险评估和针对 PFAS 的控制策略，作为进一步公共卫生研究的关键起点。