Energetics of a protein disorder–order transition in small molecule recognition
César Mendoza-Martínez, Michail Papadourakis, Salomé Llabrés, Arun A. Gupta, Paul N. Barlow, Julien Michel
Abstract
a complete thermodynamic analysis that featured adaptive absolute alchemical free energy of binding calculations with enhanced-sampling molecular dynamics simulations. The simulations reveal that in apo MDM2 the ordered lid state is energetically disfavoured. AM-7209, but not Nutlin-3a, shows a significant energetic preference for ordered lid conformations, thus shifting the balance towards ordering of the lid in the AM-7209/MDM2 complex. The methodology reported herein should facilitate broader targeting of intrinsically disordered regions in medicinal chemistry.
Topics & Concepts
ChemistryEnergeticsMoleculeFolding (DSP implementation)Molecular dynamicsSmall moleculeEnergy landscapeChemical physicsCrystallographyComputational chemistryPhysicsThermodynamicsBiochemistryOrganic chemistryElectrical engineeringEngineeringProtein Structure and DynamicsEnzyme Structure and FunctionMass Spectrometry Techniques and Applications