Dipartimento di Chimica, Materiali e Ingegneria Chimica "G. Natta", Politecnico di Milano, Via L. Mancinelli 7, 20131, Milano, Italy.
Dipartimento di Chimica, Università degli Studi di Milano, via Golgi 19, I-20133, Milano, Italy.
J Mol Graph Model. 2021 Jun;105:107886. doi: 10.1016/j.jmgm.2021.107886. Epub 2021 Mar 3.
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.
作为工业活动的副产品，二恶英（如 2,3,7,8-四氯二苯并对二恶英（TCDD））被意外释放到环境中，这对人类健康构成了主要的关注。已知接触这些化学物质会产生广泛的不良影响，包括癌症。TCDD 在人体内的主要作用机制涉及与芳烃受体（AhR）结合。尽管已经定性确定，但 TCDD 与 AhR 的结合在分子水平上仍未得到很好的描述。从最近开发的人 AhR PAS-B 结构域的结构模型出发，我们尝试通过分子动力学确定可行的 TCDD 进入人 AhR 配体结合域的途径。基于元动力学模拟的结果，我们确定了两个可能作为 TCDD 进入途径的主要区域。对于每条路径，我们都对与 TCDD 密切相互作用的残基进行了表征，从而提出了 TCDD 捕获的可能机制。我们的结果根据关于人 AhR 结构和功能的现有信息进行了审查和讨论。
