Perfluoroalkyl Acid Binding with Peroxisome Proliferator-Activated Receptors α, γ, and δ, and Fatty Acid Binding Proteins by Equilibrium Dialysis with a Comparison of Methods.
Perfluoroalkyl Acid Binding with Peroxisome Proliferator-Activated Receptors α, γ, and δ, and Fatty Acid Binding Proteins by Equilibrium Dialysis with a Comparison of Methods.
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DOI：
10.3390/toxics9030045
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发表时间：
2021-02-26
期刊：
影响因子：
4.6
通讯作者：
Ng C
中科院分区：
文献类型：
--
作者：
Khazaee M;Christie E;Cheng W;Michalsen M;Field J;Ng C
全氟和多氟烷基物质(PFAS)的生物影响与它们的蛋白质相互作用有关。现有的研究主要集中在血清白蛋白和肝脏脂肪酸结合蛋白上，用各种方法测定的结合亲和力具有很高的变异性。此外，关于短链全氟辛烷磺酸的数据很少，尽管它们在环境中的流行率正在增加。我们用分子动力学方法(MD)筛选了6个全氟烷基羧酸酯(PFCA)和3个全氟烷基磺酸盐(PFSA)与肝脏和肠道脂肪酸结合蛋白(L和I-FABP)以及过氧化物酶体增殖物激活核受体(PPAR-α，-δ和-γ)的结合。通过平衡透析(EQD)，用液相色谱串联质谱(EQD)测定了蛋白质-PFAS对的平衡解离常数。在此和文献中对来源于EQD的KDS和来自文献的其他体外方法(例如，荧光法)进行了比较。电子定量分析显示PPAR-δ与全氟丁酸酯(0.044±0.013µM)和全氟己烷磺酸盐(0.035±0.0020µM)以及PPAR-α与全氟己酸酯(0.097±0.070µM)有很强的结合。与L-FABP的结合亲和力随着链长的增加而增加不同，无论是分子动力学模拟还是EQD，PPAR的KDS都表现出很小的链长依赖性。与其他体外方法相比，基于EQD的KDS始终显示出对不同蛋白质的更高亲和力。这是第一次报道PPAR与短链PFAS与KDS在亚微摩尔范围内结合的研究。
The biological impacts of per- and polyfluorinated alkyl substances (PFAS) are linked to their protein interactions. Existing research has largely focused on serum albumin and liver fatty acid binding protein, and binding affinities determined with a variety of methods show high variability. Moreover, few data exist for short-chain PFAS, though their prevalence in the environment is increasing. We used molecular dynamics (MD) to screen PFAS binding to liver and intestinal fatty acid binding proteins (L- and I-FABPs) and peroxisome proliferator activated nuclear receptors (PPAR-α, -δ and -γ) with six perfluoroalkyl carboxylates (PFCAs) and three perfluoroalkyl sulfonates (PFSAs). Equilibrium dissociation constants, KDs, were experimentally determined via equilibrium dialysis (EqD) with liquid chromatography tandem mass spectrometry for protein-PFAS pairs. A comparison was made between KDs derived from EqD, both here and in literature, and other in vitro approaches (e.g., fluorescence) from literature. EqD indicated strong binding between PPAR-δ and perfluorobutanoate (0.044 ± 0.013 µM) and perfluorohexane sulfonate (0.035 ± 0.0020 µM), and between PPAR-α and perfluorohexanoate (0.097 ± 0.070 µM). Unlike binding affinities for L-FABP, which increase with chain length, KDs for PPARs showed little chain length dependence by either MD simulation or EqD. Compared with other in vitro approaches, EqD-based KDs consistently indicated higher affinity across different proteins. This is the first study to report PPARs binding with short-chain PFAS with KDs in the sub-micromolar range.
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影响因子：
5.4
作者：
Berger, Joel;Wagner, John A
通讯作者：
Wagner, John A
影响因子：
11.4
作者：
Guelfo, Jennifer L.;Higgins, Christopher P.
通讯作者：
Higgins, Christopher P.
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影响因子：
3.7
作者：
Batista FA;Trivella DB;Bernardes A;Gratieri J;Oliveira PS;Figueira AC;Webb P;Polikarpov I
通讯作者：
Polikarpov I
影响因子：
11.4
作者：
Cheng, Weixiao;Ng, Carla A.
通讯作者：
Ng, Carla A.
影响因子：
3
作者：
dos Santos, Jademilson Celestino;Bernardes, Amanda;Polikarpov, Igor
通讯作者：
Polikarpov, Igor