Novel Covalent Modifier-Induced Local Conformational Changes within the Intrinsically Disordered Region of the Androgen Receptor

SIMPLE SUMMARY: The androgen receptor (AR) is an important protein involved in sensing hormones. The over-activation of a class of AR can lead to cellular dysfunction and diseases such as prostate cancer. This malfunction is connected to abnormal protein clusters known as condensates. To address this, a series of novel small molecules, which can potentially dissolve AR condensates, have been tested for their ability to change the shape of the AR. These molecules interact with disordered regions of the AR and consequently, weak structural signatures are buried in a vast amount of seemingly random shapes of the AR. We use biophysical models and computational approaches to examine the shapes of the AR when it is bound to a therapeutically promising small-molecule modulator. Here, we provide insights on how subtle alterations of the small-molecule modulator can strongly affect their ability to alter AR shapes. ABSTRACT: Intrinsically disordered regions (IDRs) of transcription factors play an important biological role in liquid condensate formation and gene regulation. It is thus desirable to investigate the druggability of IDRs and how small-molecule binders can alter their conformational stability. For the androgen receptor (AR), certain covalent ligands induce important changes, such as the neutralization of the condensate. To understand the specificity of ligand–IDR interaction and potential implications for the mechanism of neutralizing liquid–liquid phase separation (LLPS), we modeled and performed computer simulations of ligand-bound peptide segments obtained from the human AR. We analyzed how different covalent ligands affect local secondary structure, protein contact map, and protein–ligand contacts for these protein systems. We find that effective neutralizers make specific interactions (such as those between cyanopyrazole and tryptophan) that alter the helical propensity of the peptide segments. These findings on the mechanism of action can be useful for designing molecules that influence IDR structure and condensate of the AR in the future.