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

Journal article

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.

Authors: Mendoza-Martinez, C; Gupta, AA; Llabrés, S; Barlow, PN; Michel, J

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Communications Chemistry
• Volume: 9
• Issue: 1
• Article number: 65
• Publication date: 2026-01-14
• Acceptance date: 2025-12-16
• DOI: 10.1038/s42004-025-01869-5
• EISSN: 2399-3669
• ISSN: 2399-3669
• Language: English
• Keywords: Small molecule; Molecular dynamics; Intrinsically disordered proteins; Moiety; Protein folding; Entropy (arrow of time); Molecule; Folding (DSP implementation); Allosteric regulation; Protein–protein interaction