Molecular Driving Force of a Small Molecule-Induced Protein Disorder-Order Transition

The selectivity and affinity of numerous protein-protein interactions depends upon the folding of intrinsically disordered regions (IDRs) that accompanies complexation. Yet there are currently no guiding principles for a similar molecular recognition strategy aimed at the design of small-molecule modulators of this category of protein-protein interactions. Herein, the molecular driving forces that underpin selective 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 hydrophobic collapse via formation of a network of non-polar contacts between a chlorophenyl moiety of AM-7209 and the lid residue I19. 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.