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

## TL;DR

This study explores how non-covalent interactions affect the toxicity of dioxins by analyzing their behavior with the AhR receptor and lipid membranes.

## Contribution

The study introduces an integrated CMD and QM/MM-EDA approach to analyze PCDD toxicity mechanisms.

## Key findings

- Toxicity correlates more with membrane permeation than AhR binding affinity.
- Non-covalent interactions significantly influence PCDD behavior in biological systems.
- Current risk assessments may underestimate dioxin impact due to overlooked physicochemical factors.

## Abstract

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-p-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.