Previous experimental and computational work has demonstrated that the N-terminal lid region of MDM2 adopts a helix-turn-strand motif in the presence of several piperidinone ligands. A panel of single-site and double-site MDM2 mutants was prepared for in silico analyses to probe the contributions to the stabilisation of this motif of various lid-to-protein and lid-toligand contacts (Figure ). Mutations to a glycine were attempted at several locations, as this residue shows significant differences in backbone conformational preferences over other amino acid residues and would be expected to increase the inherent structural disorder of the lid. Each mutant underwent two independent 0.5 μs equilibrium MD simulations, and the stability of the helical motif observed at the base of the lid was assessed by post-processing of the computed trajectories.