PPARγ helix 12 exhibits an antagonist conformation

Area of Science:

• Biochemistry
• Structural Biology
• Computational Chemistry

Background:

• Peroxisome proliferator-activated receptor γ (PPARγ) is a key nuclear receptor with largely unknown activation helix 12 (H12) conformational dynamics.
• H12 flexibility in apo PPARγ and lack of antagonists hinder experimental structural and dynamic analysis.

Purpose of the Study:

• To investigate the potential antagonist conformation of PPARγ's H12.
• To elucidate the structural and dynamic behavior of H12 in PPARγ, particularly within homodimers.

Main Methods:

• Utilized extensive accelerated molecular dynamics (aMD) simulations (≈12 μs).
• Employed metadynamics and conventional molecular dynamics (MD) runs.
• Analyzed H12 conformations in apo and homodimer PPARγ forms.

Main Results:

• Revealed that PPARγ's H12 can indeed exist in an antagonist conformation.
• Demonstrated that the antagonist and agonist states of H12 possess nearly identical free energies.
• Observed significant H12 conformational deviations in PPARγ homodimers, with asymmetric stabilization (agonist vs. agonist/antagonist exchange).

Conclusions:

• The study provides a structural and dynamic basis for the observed asymmetry in PPARγ homodimer crystal structures.
• Results suggest criteria for identifying protein regions and candidate structures for developing stable PPARγ antagonist ligands.