Investigating the Aryl Hydrocarbon Receptor Agonist/Antagonist Conformational Switch Using Well-Tempered Metadynamics...

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• The aryl hydrocarbon receptor (AhR) is a transcription factor regulating cellular functions, environmental sensing, and xenobiotic metabolism.
• AhR dysregulation is linked to diseases such as cancer and immune disorders.
• Understanding AhR's dynamic behavior is key for developing targeted therapies.

Purpose of the Study:

• To determine the 3D structure of human AhR using AI.
• To investigate AhR's conformational dynamics through molecular simulations.
• To gain atomic-level insights into AhR's functional mechanisms and ligand interactions.

Main Methods:

• Utilized artificial intelligence for 3D structure determination of human AhR.
• Performed molecular dynamics (MD) simulations to study protein conformations.
• Employed well-tempered metadynamics (WTE-metaD) to explore the conformational landscape.

Main Results:

• Obtained the 3D structure of the entire human AhR.
• Simulations revealed distinct protein conformations, offering insights into function and movement.
• Identified closed and open states of helix α1 in the bHLH domain, consistent with experimental data.
• Predicted the inactive AhR form and pinpointed Arginine 42 as a key regulatory residue.

Conclusions:

• AI and MD simulations provide atomic-level understanding of AhR's dynamic behavior.
• The study elucidates conformational changes crucial for AhR function.
• Findings contribute to developing targeted therapies for AhR-related health conditions.