组蛋白乙酰化为表观遗传学修饰的一种重要形式，全氟化合物可通过组蛋白去乙酰化酶抑制等非配体依赖受体激活作用干扰雌激素受体介导信号通路。本项目拟采用理论模拟与实验验证相结合的研究方法，重点开展污染物引发的蛋白乙酰化水平变化对雌激素受体活化作用影响的生物化学机制研究。通过同源模建构建典型组蛋白去乙酰化酶结构，基于量子力学与分子动力学相结合的方法寻找污染物与酶可能的结合模式，模拟分析疏水活性作用通道对酶活性的调控过程，揭示全氟化合物的酶选择性抑制分子基础。将全氟化合物蛋白乙酰化水平干扰活性与其对雌激素受体信号作用通路的扰动相互关联，基于不同靶点间程序调控模式进行数学建模，诠释污染物雌激素效应的关键毒性作用路径。以计算结果指导实验研究，阐明污染物引发的蛋白乙酰化水平变化对雌激素受体活化作用影响的生物化学机制，为科学评价污染物的环境危害与健康风险提供理论依据与方法贮备。

Disruption of intracellular estrogen receptor-mediated signaling via non receptor binding mechanism such as histone deacetylase inhibition play an important role for perfluorinated chemicals. In the present project, both theoretical simulation methods and necessary bioassays are adopted to explore disruption mechanism of estrogen receptor activity through histone deacetylase inhibition by perfluorinated chemicals. Specifically, homology modeling and function analysis of selected histone deacetylase will be performed to obtain the 3D-structure of the enzyme proteins, while quantum mechanics will be coupled with optimized molecular dynamics strategy to evaluate possible modes of action and reveal the inhibition mechanism involving the continuous open-close motion regulation of the acetyl-releasing channel door. Subsequently, molecular basis of histone deacetylase inhibition selectivity will be elucidated for typical perfluorinated chemicals. Furthermore, causality between estrogenic effect of pollutants and perturbation of estrogen receptor-mediated signaling induced by pathway components such as histone deacetylase and its substrate was explored to find the key toxicity pathway on the basis of estrogen receptor progressive activation. Finally, disruption mechanism of estrogen receptor activity through histone deacetylase inhibition by perfluorinated chemicals will be established and revised using both theoretical simulation results and experimental information. The exploration in the present project may provide theoretical foundation and methodology support to both health risk assessment and ecological risk assessment of chemical contaminants.