Skip to main content
Springer Nature Link
Log in

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

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Harris SL, Levine AJ (2005) Oncogene 24(17):2899

    Article  CAS  Google Scholar 

  2. Fridman JS, Lowe SW (2003) Oncogene 22(56):9030

    Article  CAS  Google Scholar 

  3. Stott FJ, Bates S, James MC, McConnell BB, Starborg M, Brookes S, Palmero I, Ryan K, Hara E, Vousden KH (1998) EMBO J 17(17):5001

    Article  CAS  Google Scholar 

  4. Unger T, Juven-Gershon T, Moallem E, Berger M, Sionov RV, Lozano G, Oren M, Haupt Y (1999) EMBO J 18(7):1805

    Article  CAS  Google Scholar 

  5. Nikolova PV, Wong KB, DeDecker B, Henckel J, Fersht AR (2000) EMBO J 19(3):370

    Article  CAS  Google Scholar 

  6. Vousden KH, Lane DP (2007) Nat Rev Mol Cell Biol 8(4):275

    Article  CAS  Google Scholar 

  7. Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Science 274(5289):948

    Article  CAS  Google Scholar 

  8. Chen HF, Luo R (2007) J Am Chem Soc 129(10):2930

    Article  CAS  Google Scholar 

  9. Popowicz GM, Czarna A, Rothweiler U, Szwagierczak A, Krajewski M, Weber L, Holak TA (2007) Cell Cycle 6(19):2386

    Article  CAS  Google Scholar 

  10. Moll UM, Petrenko O (2003) Mol Cancer Res 1(14):1001

    CAS  Google Scholar 

  11. Chi SW, Lee SH, Kim DH, Ahn MJ, Kim JS, Woo JY, Torizawa T, Kainosho M, Han KH (2005) J Biol Chem 280(46):38795

    Article  CAS  Google Scholar 

  12. Chène P (2003) Nat Rev Cancer 3(2):102

    Article  Google Scholar 

  13. Klein C, Vassilev L (2004) Br J Cancer 91(8):1415

    CAS  Google Scholar 

  14. Grönroos E, Terentiev AA, Punga T, Ericsson J (2004) Proc Natl Acad Sci USA 101(33):12165

    Article  Google Scholar 

  15. Kritzer JA, Lear JD, Hodsdon ME, Schepartz A (2004) J Am Chem Soc 126(31):9468

    Article  CAS  Google Scholar 

  16. Lee JH, Zhang Q, Jo S, Chai SC, Oh M, Im W, Lu H, Lim HS (2011) J Am Chem Soc 133:676

    Article  CAS  Google Scholar 

  17. Phan J, Li Z, Kasprzak A, Li B, Sebti S, Guida W, Schönbrunn E, Chen J (2010) J Biol Chem 285(3):2174

    Article  CAS  Google Scholar 

  18. Liu M, Li C, Pazgier M, Mao Y, Lv Y, Gu B, Wei G, Yuan W, Zhan C (2010) Proc Natl Acad Sci USA 107(32):14321

    Article  CAS  Google Scholar 

  19. Pazgier M, Liu M, Zou G, Yuan W, Li C, Li J, Monbo J, Zella D, Tarasov SG (2009) Proc Natl Acad Sci USA 106(12):4665

    Article  CAS  Google Scholar 

  20. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C (2004) Science 303(5659):844

    Article  CAS  Google Scholar 

  21. Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Källblad P, Kemp SJ (2006) J Med Chem 49(21):6209

    Article  CAS  Google Scholar 

  22. Ding K, Lu Y, Nikolovska-Coleska Z, Wang G, Qiu S, Shangary S, Gao W, Qin D, Stuckey J, Krajewski K (2006) J Med Chem 49(12):3432

    Article  CAS  Google Scholar 

  23. Shangary S, Wang S (2009) Annu Rev Pharmacol Toxicol 49:223

    Article  CAS  Google Scholar 

  24. Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J (2008) Proc Natl Acad Sci USA 105(10):3933

    Article  CAS  Google Scholar 

  25. Grasberger BL, Lu T, Schubert C, Parks DJ, Carver TE, Koblish HK, Cummings MD, LaFrance LV, Milkiewicz KL, Calvo RR (2005) J Med Chem 48(4):909

    Article  CAS  Google Scholar 

  26. Ding Y, Mei Y, Zhang JZH (2008) J Phys Chem B 112(36):11396

    Article  CAS  Google Scholar 

  27. Hu G, Wang D, Liu X, Zhang Q (2010) J Comput Aid Mol Des 24(8):687

    Article  CAS  Google Scholar 

  28. Lu SY, Jiang YJ, Zou JW, Wu TX (2011) J Mol Graph Model 30:167

    Article  CAS  Google Scholar 

  29. Chen J, Wang J, Xu B, Zhu W, Li G (2011) J Mol Graph Model 30:46

    Google Scholar 

  30. Massova I, Kollman PA (1999) J Am Chem Soc 121(36):8133

    Article  CAS  Google Scholar 

  31. Zhong H, Carlson HA (2005) Proteins 58(1):222

    Article  CAS  Google Scholar 

  32. Chen J, Zhang D, Zhang Y, Li G (2012) Int J Mol Sci 13(2):2176

    Article  CAS  Google Scholar 

  33. Espinoza-Fonseca L, Trujillo-Ferrara JG (2006) Biopolymers 83(4):365

    Article  CAS  Google Scholar 

  34. Ichiye T, Karplus M (2004) Proteins 11(3):205

    Article  Google Scholar 

  35. Levy R, Srinivasan A, Olson W, McCammon J (2004) Biopolymers 23(6):1099

    Article  Google Scholar 

  36. Laberge M, Yonetani T (2008) Biophys J 94(7):2737

    Article  CAS  Google Scholar 

  37. Amadei A, Linssen A, Berendsen HJC (2004) Proteins 17(4):412

    Article  Google Scholar 

  38. Boehr DD, Nussinov R, Wright PE (2009) Nat Chem Biol 5(11):789

    Article  CAS  Google Scholar 

  39. Wang J, Yang H, Zuo Z, Yan X, Wang Y, Luo X, Jiang H, Chen K, Zhu W (2010) J Phys Chem B 114(46):15172

    Article  CAS  Google Scholar 

  40. Wu EL, Han KL, Zhang JZH (2008) Chem A Eur J 14(28):8704

    Article  CAS  Google Scholar 

  41. Chen J, Zhang S, Liu X, Zhang Q (2010) J Mol Model 16(3):459

    Article  Google Scholar 

  42. Kar P, Knecht V (2012) J Phys Chem B 116(8):2605

    Article  CAS  Google Scholar 

  43. Meher BR, Wang Y (2012) J Phys Chem B 116(6):1884

    Article  CAS  Google Scholar 

  44. Czarna A, Popowicz GM, Pecak A, Wolf S, Dubin G, Holak TA (2009) Cell Cycle 8(8):1176

    Article  CAS  Google Scholar 

  45. Popowicz GM, Czarna A, Wolf S (2010) Cell Cycle 9(6):1104

    Article  CAS  Google Scholar 

  46. Case DA, Darden TA, Cheatham III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts S, Hayik S, Roitberg A, Seabra G, Swails J, GÖtz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2012) AMBER 12, University of California, San Francisco

  47. Duan Y, Wu C, Chowdhury S, Lee MC, Xiong G, Zhang W, Yang R, Cieplak P, Luo R, Lee T (2003) J Comput Chem 24(16):1999

    Article  CAS  Google Scholar 

  48. Jakalian A, Jack DB, Bayly CI (2002) J Comput Chem 23(16):1623

    Article  CAS  Google Scholar 

  49. Jakalian A, Bush BL, Jack DB, Bayly CI (2000) J Comput Chem 21(2):132

    Article  CAS  Google Scholar 

  50. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25(9):1157

    Article  CAS  Google Scholar 

  51. Coleman TG, Mesick HC, Darby RL (1977) Ann Biomed Eng 5(4):322

    Article  CAS  Google Scholar 

  52. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089

    Article  CAS  Google Scholar 

  53. Essmann U, Perera L, Berkowitz ML, Darden T, Lee H, Pedersen LG (1995) J Chem Phys 103(19):8577

    Article  CAS  Google Scholar 

  54. Case DA, Cheatham TE, Darden T, Gohlke H, Luo R, Merz KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) J Comput Chem 26(16):1668

    Article  CAS  Google Scholar 

  55. Miller BR III, McGee TD, Swails JM, Homeyer N, Gohlke H, Roitberg AE (2012) J Chem Theory Comput 8(9):3314

    Article  CAS  Google Scholar 

  56. Onufriev A, Bashford D, Case DA (2004) Proteins 55(2):383

    Article  CAS  Google Scholar 

  57. Gohlke H, Kiel C, Case DA (2003) J Mol Biol 330(4):891

    Article  CAS  Google Scholar 

  58. Weiser J, Shenkin PS, Still WC (1999) J Comput Chem 20(2):217

    Article  CAS  Google Scholar 

  59. Uhrinova S, Uhrin D, Powers H, Watt K, Zheleva D, Fischer P, McInnes C, Barlow PN (2005) J Mol Biol 350(3):587

    Article  CAS  Google Scholar 

  60. Barrett CP, Hall BA, Noble MEM (2004) Acta Cryst 60(12):2280

    Google Scholar 

  61. Campos SR, Machuqueiro M, Baptista AM (2010) J Phys Chem B 114(39):12692

    Article  CAS  Google Scholar 

  62. Joseph TL, Madhumalar A, Brown CJ, Lane DP, Verma C (2010) Cell Cycle 9(6):1167

    Article  CAS  Google Scholar 

  63. Chen J, Yang M, Hu G, Shi S, Yi C, Zhang Q (2009) J Mol Model 15(10):1245

    Article  CAS  Google Scholar 

  64. Chong LT, Duan Y, Wang L, Massova I, Kollman PA (1999) Proc Natl Acad Sci USA 96(25):14330

    Article  CAS  Google Scholar 

  65. Xu Y, Wang R (2006) Proteins 64(4):1058

    Article  CAS  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Jianzhong Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Jinan Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Weiliang Zhu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Guohui Li
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Jianzhong Chen or Guohui Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords