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

Area of Science:

• Molecular Biology
• Biophysics
• Computational Chemistry

Background:

• Intrinsically disordered regions (IDRs) in transcription factors are crucial for liquid condensate formation and gene regulation.
• Investigating the druggability of IDRs and how small molecules affect their stability is important for therapeutic development.
• Covalent ligands targeting the androgen receptor (AR) can neutralize its associated condensates.

Purpose of the Study:

• To understand the specificity of ligand-IDR interactions for the human AR.
• To elucidate the mechanism by which small molecules neutralize liquid-liquid phase separation (LLPS) of AR.
• To explore the potential for designing novel molecules that modulate AR IDR structure and condensate formation.

Main Methods:

• Computer simulations were performed on peptide segments from the human AR bound to various covalent ligands.
• Analysis focused on the effects of ligands on local secondary structure, protein contact maps, and protein-ligand contacts.
• Investigated specific interactions, such as cyanopyrazole and tryptophan, to understand their role in modulating IDR properties.

Main Results:

• Different covalent ligands exert distinct effects on the conformational properties of AR peptide segments.
• Effective neutralizers form specific interactions, like cyanopyrazole with tryptophan, which significantly alter the helical propensity of the IDRs.
• These specific interactions are key to understanding the mechanism of LLPS neutralization.

Conclusions:

• Specific ligand-IDR interactions are critical for modulating the structure and function of intrinsically disordered regions.
• The findings provide insights into the mechanism by which certain small molecules neutralize AR liquid-liquid phase separation.
• This knowledge can guide the future design of targeted therapeutics aimed at influencing AR IDR structure and condensate dynamics.