title: Characterizing the Free-Energy Landscape of MDM2 Protein-Ligand Interactions by Steered Molecular Dynamics Simulations.
abstract: Inhibition of p53-MDM2 interaction by small molecules is considered to be a promising approach to re-activate wild-type p53 for tumor suppression. Several inhibitors of the MDM2-p53 interaction were designed and studied by the experimental methods and the molecular dynamics simulation. However, the unbinding mechanism was still unclear. The steered molecular dynamics simulations combined with Brownian dynamics fluctuation-dissipation theorem were employed to obtain the free-energy landscape of unbinding between MDM2 and their four ligands. It was shown that compounds 4 and 8 dissociate faster than compounds 5 and 7. The absolute binding free energies for these four ligands are in close agreement with experimental results. The open movement of helix II and helix IV in the MDM2 protein-binding pocket upon unbinding is also consistent with experimental MDM2-unbound conformation. We further found that different binding mechanisms among different ligands are associated with H-bond with Lys51 and Glu25. These mechanistic results may be useful for improving ligand design.
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics, Dezhou University, Dezhou, China.|College of Physics and Electronic Information, Dezhou University, Dezhou, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Hu
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics, Dezhou University, Dezhou, China.|College of Physics and Electronic Information, Dezhou University, Dezhou, China.
authors.forename: Shicai
authors.initials: S
authors.lastname: Xu
authors.affiliation: Shandong Provincial Key Laboratory of Functional Macromolecular Biophysics, Dezhou University, Dezhou, China.|College of Physics and Electronic Information, Dezhou University, Dezhou, China.
authors.forename: Jihua
authors.initials: J
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2 protein; steered molecular dynamics simulations; unbinding mechanism