Unravelling the Role Played by Non-covalent Interactions in the Action Mechanism of PCDDs within Cells

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates biological signals and regulates diverse cellular functions. Of particular concern are the effects triggered by dioxins and dioxin-like compounds (DLCs), whose toxicological outcomes arise through both canonical and noncanonical pathways, leading to the designation of AhR as the "dioxin receptor". However, conventional risk assessment approaches based on toxic equivalency factors (TEFs), which primarily reflect the capacity of these compounds to bind and activate AhR, do not fully account for critical aspects such as environmental concentration and bioavailability, potentially underestimating their true impact. In this work, we present a comparative analysis of polychlorinated dibenzo-<i>p</i>-dioxins (PCDDs) with varying degrees of chlorination, focusing on their interactions with the AhR at the ligand-binding domain and on their permeation abilities across a model lipid membrane. To this end, we combine classical molecular dynamics (CMD) simulations with a hybrid quantum mechanics/molecular mechanics energy decomposition analysis (QM/MM-EDA) framework. This integrated approach enables a molecular-level characterization of receptor binding affinities and membrane permeation efficiencies. Our findings provide novel insights into the mechanisms underlying the relative toxicity of DLCs and highlight the need for integrative assessment strategies that encompass both receptor-ligand interactions and physicochemical behavior in biological environments. It is noteworthy that the toxicity of these compounds, as quantified by the pEC₅₀ index, correlates with the membrane permeation barrier rather than with AhR binding affinity, identifying permeation as the key mechanistic step in the toxicological process of these compounds.