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

Small-molecule inhibitors stabilize oligomeric interfaces of the intrinsically disordered androgen receptor activation domain, with mechanisms resolved by long-timescale all-atom MD and NMR.

• Why it matters: Understanding how these inhibitors reshape dynamic, heterogeneous intermolecular contacts is needed to explain differing drug potencies and guide design for disordered proteins.
• What they did: The study combined long-timescale all-atom molecular dynamics simulations with nuclear magnetic resonance spectroscopy to characterize how inhibitors stabilize oligomerization interfaces of the androgen receptor activation domain.
• The result: The identified mechanisms explain the relative potencies of androgen receptor activation domain inhibitors and suggest general strategies for designing small molecules targeting oligomeric, and potentially condensed, forms of intrinsically disordered proteins.

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