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

Abstract

Small molecule inhibitors of the intrinsically disordered androgen receptor activation domain have been tested in clinical trials for the treatment of castration-resistant prostate cancer. These compounds have been shown to stabilize oligomeric forms of the androgen receptor activation domain in solution and alter the properties of androgen receptor condensates. The molecular mechanisms by which small molecules modulate these processes have been poorly understood in atomic detail. Here, we use long-timescale all-atom molecular dynamics (MD) simulations and nuclear magnetic resonance (NMR) spectroscopy to determine how small molecules stabilize highly dynamic, heterogeneous intermolecular interfaces that mediate oligomerization of the androgen receptor activation domain. The mechanisms determined here explain the relative potencies of androgen receptor activation domain inhibitors and suggest general strategies for designing small molecules that target oligomeric and, potentially, condensed forms of intrinsically disordered proteins.