title: Microsecond simulations of mdm2 and its complex with p53 yield insight into force field accuracy and conformational dynamics.
abstract: The p53-MDM2 complex is both a major target for cancer drug development and a valuable model system for computational predictions of protein-ligand binding. To investigate the accuracy of molecular simulations of MDM2 and its complex with p53, we performed a number of long (200 ns to 1 µs) explicit-solvent simulations using a range of force fields. We systematically compared nine popular force fields (AMBER ff03, ff12sb, ff14sb, ff99sb, ff99sb-ildn, ff99sb-ildn-nmr, ff99sb-ildn-phi, CHARMM22*, and CHARMM36) against experimental chemical shift data, and found similarly accurate results, with microsecond simulations achieving better agreement compared to 200-ns trajectories. Although the experimentally determined apo structure has a closed binding cleft, simulations in all force fields suggest the apo state of MDM2 is highly flexible, and able to sample holo-like conformations, consistent with a conformational selection model. Initial structuring of the MDM2 lid region, known to competitively bind the binding cleft, is also observed in long simulations. Taken together, these results show molecular simulations can accurately sample conformations relevant for ligand binding. We expect this study to inform future computational work on folding and binding of MDM2 ligands.
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, Pennsylvania, 19122.
authors.forename: George A
authors.initials: GA
authors.lastname: Pantelopulos
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, Pennsylvania, 19122.
authors.forename: Sudipto
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, Pennsylvania, 19122.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Voelz
mesh_terms: D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D025341:Principal Component Analysis; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2 lid region; chemical shift prediction; molecular dynamics; protein binding; receptor flexibility