How small molecules stabilize oligomers of a phase-separating disordered protein

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Small molecule inhibitors targeting the androgen receptor activation domain (AR-AD) are in clinical trials for castration-resistant prostate cancer.
• These inhibitors stabilize AR-AD oligomers and alter condensate properties, but their atomic-level mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms by which small molecules stabilize intrinsically disordered AR-AD oligomers.
• To provide insights for designing novel small molecules targeting intrinsically disordered proteins.

Main Methods:

• Long-timescale all-atom molecular dynamics (MD) simulations.
• Nuclear magnetic resonance (NMR) spectroscopy.

Main Results:

• Small molecules stabilize dynamic, heterogeneous intermolecular interfaces essential for AR-AD oligomerization.
• The study explains the varying potencies of AR-AD inhibitors.

Conclusions:

• The determined mechanisms offer strategies for designing small molecules targeting oligomeric and condensed forms of intrinsically disordered proteins.
• This work advances the understanding of AR-AD inhibition for prostate cancer therapy.