Energetics of a protein disorder-order transition in small molecule recognition

Many proteins recognise other proteins via mechanisms that involve the folding of intrinsically disordered regions upon complex formation. Such is the case of the binding of the compound AM-7209, which has been reported to confer order upon an intrinsically disordered ‘lid’ region of the oncoprotein MDM2 in opposition to the binding of the ligand Nutlin-3a. We investigated the energetics of this ordering process via ITC calorimetry, adaptive absolute alchemical free energy of binding calculations and enhanced-sampling molecular dynamics simulations.

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