分子动力学模拟揭示PFAS诱导PPARα激活的分子机制
Molecular Dynamics Simulation Reveals the Molecular Mechanism of PFAS-induced PPARα Activation
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摘要: 全/多氟烷基化合物(PFAS)可通过激活过氧化物酶体增殖物激活受体α (PPARα)诱导肝毒性，然而PFAS与PPARα相互作用的分子机制尚不清晰。本研究基于高斯加速分子动力学(GaMD)和分子力学-广义波恩表面积法(MM-GBSA)，计算了7种传统和新型PFAS与PPARα的结合自由能(ΔGbind)，结果发现ΔGbind与PFAS激活PPARα的半数效应浓度的对数值(logEC50)之间存在显著的相关性(r=0.82, P<0.05)。此外，氟化碳原子的数量与ΔGbind正相关，且含羧基的PFAS的ΔGbind通常比含磺酸基的PFAS更低。通过分析结构稳定性、氢键分布和配体-残基接触，揭示了PFAS的激活活性与其在PPARα口袋内的结合模式直接相关。活性较强的PFAS，优先结合到由螺旋(H) H3, H7, H11和H12组成的口袋中，与ILE354, HIS440和CYS276等关键残基形成相互作用。结果有助于筛选具有PPARα激活效应的PFAS，支持PFAS类化学品的毒性效应评估。
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关键词:
- 全/多氟烷基化合物 /
- 过氧化物酶体增殖物激活受体α /
- 肝毒性 /
- 分子动力学
Abstract: Per- and polyfluoroalkyl substances (PFAS) could induce hepatotoxicity through the activation of peroxisome proliferator-activated receptor α (PPARα). However, the molecular mechanism of PFAS-induced PPARα activation remains unclear. This study calculated the binding free energy (ΔGbind) of seven legacy and emerging PFASs with PPARα based on Gaussian accelerated molecular dynamics (GaMD) and molecular mechanics-generalized Born surface area (MM-GBSA). The results indicated a significant correlation (r=0.82, P<0.05) between ΔGbind and the logarithmic value of half maximal effective concentration (logEC50) of PFAS activating PPARα. Additionally, the number of fluorocarbon atoms positively correlated with ΔGbind, and PFAS containing carboxyl groups generally had a lower ΔGbind compared to those containing sulfonate groups. The activation activity of PFAS towards PPARα was found to be directly associated with their binding patterns within the PPARα ligand-binding pocket, as revealed through the analysis of structural stability, hydrogen bond distribution and ligand-residue contacts. PFAS with stronger activities were observed to preferentially bind within the pocket composed of H3, H7, H11 and H12, interacting with key residues such as ILE354, HIS440 and CYS276. These results contribute to the screening of PFAS with PPARα activation effect, and support the evaluation of toxic effects of PFAS. -
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