Book of Abstracts: Albany 2011

category image Albany 2011
Conversation 17
June 14-18 2011
©Adenine Press (2010)

Flexibility and Modulations in Protein-Protein Interactions: Mechanistic Insights from Molecular Dynamics Simulations of MDM2 and p53

The p53 protein provides a protection mechanism to cells against cancer (1). In normal cells p53 is complexed and down-regulated by another protein MDM2. In damaged cells the process is interrupted by stress signals that activate p53’s network, whose dysfunction is associated with cancers. Inhibiting over-expressed MDM2 to up-regulate p53’s function is a promising therapeutic strategy which will involve design of ligands to inhibit MDM2. In order to accomplish this one can employ modeling and molecular dynamics (2-5) approaches.

In this presentation, it will be shown how modeling and MD simulations have extracted the dynamics of interactions between MDM2-p53 in atomistic detail and have revealed the mechanisms that yield tight binding peptides to inhibit MDM2 (6). The simulations have attributed the flexibility and the conformational modulations to be key players which lead to the multiple mechanisms of binding associated with varying thermodynamic origins (6). Switching between electrostatics and van dar Waals components of interactions bring the uncomplexed MDM2 and p53 to each other to encounter, leading to transition to the complexed state (7, 8). Taking this system as an example, MD studies suggest that consideration of the detailed dynamics is essential to gain mechanistic insights about the plasticity of such systems and to yield improved strategies for ligand design. Atomistic insight into the effect of post-translational modifications of MDM2 on p53 regulations will also be discussed (9)


  1. B. Vogelstein, D. Lane, A. Levine, Nature 408, 307–310 (2000).
  2. P. Sklenovský and M. Otyepka, J Biomol Struct Dyn 27, 521-540 (2010).
  3. M. J. Aman, H. Karauzum, M.G. Bowden and T.L. Nguyen, J Biomol Struct Dyn 28, 1-12 (2010).
  4. C. Koshy, M. Parthiban and R. Sowdhamini. J Biomol Struct Dyn 28, 71-83 (2010).
  5. Y. Tao, Z. H. Rao and S. Q. Liu. J Biomol Struct Dyn 28, 143-158 (2010).
  6. S. G. Dastidar, D. P. Lane and C. S. Verma, J. Am. Chem. Soc., 130, 13514-13515 (2008).
  7. S. G. Dastidar, D. P. Lane, C. S. Verma, BMC Bioinformatics 10 (Suppl 15):S6 (2009)
  8. S. G. Dastidar et al., Theor. Chem. Acc. 125, 621 (2010).
  9. S. G. Dastidar et al., Cell Cycle (In Pess).

Shubhra Ghosh Dastidar

Bose Institute, Kolkata 700054, India