Unintentionally released in the environment as by-products of industrial activities, dioxins, exemplified by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), represent a primary concern for human health. Exposure to these chemicals is known to produce a broad spectrum of adverse effects, including cancer. The main mechanism of action of TCDD in humans involves binding to the Aryl hydrocarbon Receptor (AhR). Although qualitatively established, TCDD capture by the AhR remains poorly characterized at the molecular level. Starting from a recently developed structural model of the human AhR PAS-B domain, in this work we attempt the identification of viable TCDD access pathways to the human AhR ligand binding domain by means of molecular dynamics. Based on the result of metadynamics simulations, we identify two main regions that may potentially serve as access paths for TCDD. For each path, we characterize the residues closely interacting with TCDD, thereby suggesting a possible mechanism for TCDD capture. Our results are reviewed and discussed in the light of the available information about Human AhR structure and functions.

二恶英无意地作为工业活动的副产品释放到环境中，例如2,3,7,8-四氯二苯并-对-二恶英（TCDD），代表了人类健康的首要问题。已知接触这些化学物质会产生广泛的不良反应，包括癌症。TCDD在人类中的主要作用机制涉及与芳烃受体（AhR）的结合。尽管已定性确定，但AhR捕获TCDD的分子水平仍很差。从最近开发的人类AhR PAS-B结构域的结构模型开始，在这项工作中，我们尝试通过分子动力学方法确定通往人类AhR配体结合域的可行TCDD通路。根据元动力学模拟的结果，我们确定了两个主要区域，它们有可能充当TCDD的访问路径。对于每条路径，我们都表征了与TCDD紧密相互作用的残基，从而提出了TCDD捕获的可能机制。我们的结果是根据有关人类AhR结构和功能的可用信息进行回顾和讨论的。