Structural, Thermodynamic, and Dynamic Descriptors for the Differential Mechanism of HIF-2 Activity Modulators.

Area of Science:

• Biochemistry and Molecular Biology
• Structural Biology
• Pharmacology

Background:

• Hypoxia-inducible factors (HIFs) are crucial for cellular adaptation to low oxygen.
• Modulating HIF-2 activity offers therapeutic potential for various diseases.
• Understanding ligand interactions with HIF-2/ARNT is key for drug development.

Purpose of the Study:

• To elucidate the molecular mechanism behind differential HIF-2 ligand effects on the HIF-2/ARNT complex.
• To investigate how ligands influence complex stability, DNA binding, and transcriptional activity.
• To develop a multiscale approach for high-throughput virtual screening of HIF-2 ligands.

Main Methods:

• All-atom molecular dynamics (MD) simulations.
• Network-based analysis of residue correlations.
• Analysis of ligand-induced conformational changes and their impact on protein dynamics.

Main Results:

• Ligands differentially alter HIF-2/ARNT binding site conformation, affecting heterodimer stability through enthalpic and entropic changes.
• Ligand binding impacts the structure and dynamics of the DNA-binding domain, influencing hypoxia response element (HRE) binding.
• A conserved allosteric communication network mediates signal propagation between ligand-binding and DNA-binding domains.

Conclusions:

• Ligand-dependent modulation of HIF-2/ARNT structure and dynamics is critical for its transcriptional activity.
• The identified communication network provides insights into allosteric regulation.
• A multiscale approach can guide the rational design of ligands for targeted HIF-2 pathway modulation.