Molecular dynamics simulations, guided by experimental information (Zondlo et al. Biochemistry 2006, 45, 11945-11957) have been used successfully to reproduce experimental trends in binding affinities of variant p53 peptides with MDM2. Simulations reveal how the conformations of the peptides and the receptor modulate each other to optimize interactions. The conformations of the uncomplexed peptides are governed by a combination of helix and intrinsic disorder (in agreement with experiments), while in the complexed state two very different conformations can coexist. This yields very similar binding affinities, driven by either enthalpy or entropy.

The dynamics of water around a biomolecular surface has attracted a lot of attention recently. We report here protein-solvent simulation studies of the small globular protein ubiquitin (human). The simulations are run unconstrained, without freezing the bonds. The mean square displacements of the water oxygen atoms show a sublinear trend with time. The diffusion coefficient data indicate that the water in the first hydration layer behaves like water at a temperature that is roughly 12 degrees C lower than the average temperature of the system (27 degrees C). Both the dipolar second-rank relaxation and the survival time correlation function of the water layers show two decay constants, indicating contributions from fast and slow dynamics. A calculation of the interaction energy between the water layers and protein indicates that the interaction energy sharply decreases beyond 4 A from the protein surface.

BackgroundThe 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.ResultsMolecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states with only the former enabling complex formation. When both p53 and MDM2 are in near native conformations, complex formation is rapid and is driven by the formation of a hydrogen bond between W23 of p53 and L54 of MDM2 or by the embedding of F19 of p53 into MDM2. The transition of Y100 from "closed" to "open" can increase the size of the binding site. Interconversions between these two states can be induced by the N-terminal region of MDM2 or by the conformations of the p53 peptides.ConclusionMolecular dynamics simulations have revealed how the binding of p53 to MDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2. The mobility of this residue can be modulated by the conformations of p53 and the Nterminal lid region of MDM2.