# Molecular driving force of a small molecule-induced protein disorder-order transition

## TL;DR

This paper explores how a small molecule induces structural changes in a disordered region of a cancer-related protein, revealing insights into drug resistance and ligand design.

## Contribution

The study identifies non-polar interactions as a key driver of disorder-to-order transitions in protein IDRs induced by small molecules.

## Key findings

- Mutations distant from the ligand-binding site can modulate drug potency by up to three orders of magnitude.
- Non-polar contacts between AM-7209 and MDM2's I19 residue are crucial for IDR ordering.
- The study highlights the role of IDRs in drug resistance and provides new strategies for ligand optimization.

## Abstract

The selectivity and affinity of numerous protein–protein interactions depends upon the folding of intrinsically disordered regions (IDRs) that accompanies complexation. Here we investigate how folding-on-binding of a protein IDR by small molecules is facilitated by synergestic exploitation of interactions with a folded protein region. To this end, the molecular driving forces that underpin ordering of the N-terminal intrinsically disordered ‘lid’ region of the oncoprotein MDM2 by the small molecule AM-7209 were elucidated by a combination of molecular dynamics simulations, calorimetry and NMR measurements. Strikingly, mutations of lid residues distant from the ligand-binding site modulate potency by up to three orders of magnitude. A key requirement for conversion of this IDR into an ordered motif is collective stabilisation of a network of non-polar contacts between a chlorophenyl moiety of AM-7209 and the lid residue I19 to overcome conformational entropy loss associated with folding of the IDR. Our findings underscore the crucial role that protein IDRs can play in drug-resistance mechanisms and expand strategies available to medicinal chemists for ligand optimisation endeavours.

Protein–protein interactions often rely on the folding of intrinsically disordered regions (IDRs) during complexation. Here, the authors reveal how small molecule AM-7209 induces folding of the MDM2 oncoprotein’s IDR through non-polar interactions, by combining molecular dynamics simulations, calorimetry and NMR measurements.