Premium
Characterizing the Free‐Energy Landscape of MDM2 Protein–Ligand Interactions by Steered Molecular Dynamics Simulations
Author(s) -
Hu Guodong,
Xu Shicai,
Wang Jihua
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12598
Subject(s) - molecular dynamics , energy landscape , brownian dynamics , chemistry , ligand (biochemistry) , small molecule , biophysics , dynamics (music) , mdm2 , molecule , helix (gastropod) , thermodynamic integration , computational chemistry , chemical physics , brownian motion , physics , biology , biochemistry , receptor , ecology , organic chemistry , quantum mechanics , snail , gene , acoustics
Inhibition of p53– MDM 2 interaction by small molecules is considered to be a promising approach to re‐activate wild‐type p53 for tumor suppression. Several inhibitors of the MDM 2–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 MDM 2 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 MDM 2 protein‐binding pocket upon unbinding is also consistent with experimental MDM 2‐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.