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A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings

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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 α2 and β strand (β3), 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.

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Acknowledgments

This work is supported by the National Natural Science Foundation of China (11104164, 11274206 and 31200545), Dr. Start-up Foundation of Shandong Jiaotong University and Natural Science Foundation of Shandong Jiaotong University.

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Authors and Affiliations

  1. School of Science, Shandong Jiaotong University, Jinan, 250014, China

    Jianzhong Chen

  2. Shanghai Institute of Materia Medica, Drug Discovery and Design Center, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Jinan Wang & Weiliang Zhu

  3. Laboratory of Molecular Modeling and Design, State Kay Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China

    Guohui Li

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  1. Jianzhong Chen
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  2. Jinan Wang
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  3. Weiliang Zhu
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  4. Guohui Li
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Correspondence to Jianzhong Chen or Guohui Li.

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Chen, J., Wang, J., Zhu, W. et al. A computational analysis of binding modes and conformation changes of MDM2 induced by p53 and inhibitor bindings. J Comput Aided Mol Des 27, 965–974 (2013). https://doi.org/10.1007/s10822-013-9693-z

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  • DOI: https://doi.org/10.1007/s10822-013-9693-z

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