A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings
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A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings Jianzhong Chen • Jinan Wang • Weiliang Zhu Guohui Li
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Received: 20 August 2013 / Accepted: 17 November 2013 / Published online: 22 November 2013 Springer Science+Business Media Dordrecht 2013
Abstract Molecular dynamics (MD) simulations followed by principal component analysis were performed to study the conformational change of MDM2 induced by p53 and two inhibitor (P4 and MI63a) bindings. The results show that the hydrophobic cleft of MDM2 is very flexible and adaptive to different structural binding partners. The cleft tends to become wider and more stable as MDM2 binds to the three binding partners, while unbound MDM2 shows a narrower and pretty flexible cleft, which agrees with recent experimental data and theoretical studies. It was also found that the binding of P4 and p53 stabilizes the motion of the loop L2 linking the helix a2 and b strand (b3), but the presence of MI63a makes the motion of L2 disordered. In addition, the binding free energies of the three partners to MDM2 were calculated using molecular mechanics generalized Born surface area to explain the binding modes of these three partners to MDM2. This study will be helpful not only for better understanding the functional, concerted motion of MDM2, but also for the rational design of potent anticancer drugs targeting the p53–MDM2 interaction.
J. Chen (&) School of Science, Shandong Jiaotong University, Jinan 250014, China e-mail: [email protected]; [email protected] J. Wang W. Zhu Shanghai Institute of Materia Medica, Drug Discovery and Design Center, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China G. Li (&) Laboratory of Molecular Modeling and Design, State Kay Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China e-mail: [email protected]
Keywords p53–MDM2 interaction Molecular dynamics simulation PCA MM-GBSA
Introduction Important functions of the tumor suppressor p53 are to regulate cell cycle, initiate apopotosis and repair DNA [1, 2]. Active p53 also plays a pivotal role in maintaining genomic integrity of cells and preventing tumor development. In normal cells, the level of p53 is tightly regulated by the oncoprotein MDM2 via a key negative feed back loop [3, 4]. Indeed, the loss of p53 wild-type activity in cancer cells is due to two common mechanisms: one is point mutations in P53 genes, another is functional inhibition by negative regulator MDM2 [5]. Recent studies suggested that the restoration of endogenous p53 activity can efficiently inhibit the growth of cancer cells [6]. Thus, chemical compounds capable of activating p53 signal pathway are considered to be a new class of promising anticancer drugs. The structural basis of the p53–MDM2 interaction has been well studied [7]. X-ray structures show that p53 peptides prefer a helical structure in the p53–MDM2 complexes [7–9]. P53 interacts with MDM2 by insertin
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