Alvarado Raúl, Cárdenas Gustavo, Nogueira Juan J, Ramos-Berdullas Nicolás, Mandado Marcos
Department of Physical Chemistry, University of Vigo, Lagoas-Marcosende s/n, 36310 Vigo, Spain.
Department of Chemistry, Universidad Autónoma de Madrid, Calle Francisco Tomás y Valiente, 7, 28049 Madrid, Spain.
Membranes (Basel). 2022 Dec 25;13(1):28. doi: 10.3390/membranes13010028.
The permeation of dioxin-like pollutants, namely, chlorinated dibenzodioxins and dibenzofurans, through lipid membranes has been simulated using classic molecular dynamics (CMD) combined with the umbrella sampling approach. The most toxic forms of chlorinated dibenzodioxin and dibenzofuran, 2,3,7,8-tetrachloro-p-dibenzodioxin (TCDD) and 2,3,7,8-tetrachlorodibenzofuran (TCDF), and a dioleyl-phosphatidylcholine (DOPC) lipid membrane of 50 Å wide have been chosen for our study. The free energy profile shows the penetration process is largely favoured thermodynamically (ΔG ≈ -12 kcal/mol), with a progressively decrease of the free energy until reaching the energy minima at distances of 8 Å and 9.5 Å from the centre of the membrane for, respectively, TCDD and TCDF. At the centre of the membrane, both molecules display subtle local maxima with free energy differences of 0.5 and 1 kcal/mol with respect to the energy minima for TCDD and TCDF, respectively. Furthermore, the intermolecular interactions between the molecules and the lipid membrane have been characterized at the minima and the local maxima using hybrid quantum mechanics/molecular mechanics energy decomposition analysis (QM/MM-EDA). Total interaction energies of -17.5 and -16.5 kcal/mol have been found at the energy minima for TCDD and TCDF, respectively. In both cases, the dispersion forces govern the molecule-membrane interactions, no significant changes have been found at the local maxima, in agreement with the classical free energy profile. The small differences found in the results obtained for TCDD and TCDF point out that the adsorption and diffusion processes through the cell membrane are not related to the different toxicity shown by these pollutants.
已使用经典分子动力学（CMD）结合伞形抽样方法模拟了二噁英类污染物（即氯代二苯并二噁英和二苯并呋喃）通过脂质膜的渗透过程。我们选择了毒性最强的氯代二苯并二噁英和二苯并呋喃形式，即2,3,7,8 - 四氯对二苯并二噁英（TCDD）和2,3,7,8 - 四氯二苯并呋喃（TCDF），以及宽度为50 Å的二油酰磷脂酰胆碱（DOPC）脂质膜进行研究。自由能分布表明渗透过程在热力学上非常有利（ΔG ≈ -12 kcal/mol），自由能逐渐降低，直到TCDD和TCDF分别从膜中心起8 Å和9.5 Å处达到能量最小值。在膜中心，两种分子均显示出微妙的局部最大值，相对于TCDD和TCDF的能量最小值，自由能差分别为0.5和1 kcal/mol。此外，使用量子力学/分子力学混合能量分解分析（QM/MM - EDA）在最小值和局部最大值处表征了分子与脂质膜之间的分子间相互作用。在TCDD和TCDF的能量最小值处分别发现总相互作用能为-17.5和-16.5 kcal/mol。在这两种情况下，色散力主导分子与膜的相互作用，在局部最大值处未发现显著变化，这与经典自由能分布一致。TCDD和TCDF结果中的微小差异表明，通过细胞膜的吸附和扩散过程与这些污染物所表现出的不同毒性无关。
