Study of MDM2 binding to p53-analogues: Affinity, helicity, and applicability to drug design

MDM2 is a key regulator of the p53 tumor-suppressor protein. Here we study the effect of modifications of a p53 N-terminal fragment on its binding to MDM2, using implicit-solvent MD and MM-GB/S A calculations. We provide interpretation of existing experimental data and predict the effect of mutations on binding. Notably 1) We analyze the effect of regulatory phosphorylations at Ser/Thr residues and suggest that a balance between favorable electrostatics and desolvation penalties determines the effect of phosphorylation; 2) We compare the helical stability in solution of p53 alanine mutants and propose a helix stabilizing role for several residues involved in hydrogen bonding and hydrophobic packing; 3) We obtain good correlations between calculated and experimental affinities for a set of peptidomimetic inhibitors, both alone and in combination with p53 analogues, demonstrating potential applicability to drug design. From the technical aspect, protocol optimization and selection of simulation tools are addressed in detail. To the best of our knowledge this is the first published example of MM-GB/S A calculations utilizing a conformational ensemble generated with implicit solvent MD. Our results suggest that this highly efficient variant of classical explicit-solvent MM-GB/SA may be used for studying protein-protein interactions and for the design of peptidomimetic drugs.