The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. In tumours with overexpressed MDM2, the p53-MDM2 interaction can be interrupted by a peptide or small molecule to stabilize p53 as a therapeutic strategy. Structural and biochemical/mutagenesis data show that p53 has 3 hydrophobic residues F19, W23 and L26 that embed into the ligand binding pocket of MDM2 which is highly plastic in nature and can modulate its size to accommodate a variety of ligands. This binding pocket is primarily dependent on the orientation of a particular residue, Y100. We have studied the role of the dynamics of Y100 in p53 recognition.