Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

QM-MM simulations on p53-DNA complex: Comparison of DNA-binding property between cancer and their rescue mutants

p53 is a transcription factor involved in expression of a number of downstream genes in response to genotoxic stress. In normal cells, it is present in the latent or inactive state and in case of cancer cells it is activated by various post translation modifications. It is found to be mutated in 50% of the cancers. These mutations occur at a high frequency in the DNA binding region of the p53. All the seven hot spot cancer mutations R175H, Y220C, G245S, R248Q, R249S, R273C and R282W have been studied here using quantum and molecular mechanics (QM-MM) hybrid simulations. The experimentally proven rescue mutations of the above mentioned cancer mutants have also been included in the present work. Each of the p53 mutant has been simulated for 30 ns each. A comparative study of these cancer mutations along with wild type and their rescue mutations have been studied. The key residues which contribute to the binding of the p53 to the DNA by forming crucial hydrogen bonds have been studied in detail. Free energy changes, principal component analysis (PCA), hydrogen bonding and various other structural parameters have been calculated to quantify the loss and gain in DNA binding property and local structural alterations of all the p53 mutants.


Figure description: At 30th ns: Loop 2 region of wild type (blue),G245S (cancer mutant, red) and G245S_H178Y (Rescue Mutant, green) superimposed on crystal structure of p53 (PDB ID: 1TSR).


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    Nikolova PV, Wong KB, DeDecker B, Henckel J, Fersht AR, (2000) Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J 19:370-378. Lu Q, Tan Y-H., Luo R,(2007) Molecular dynamics simulations of p53 DNA-binding domain. J Phys Chem B 111(39):11538- 11545.

Shruti Koulgi
Archana Achalere
Neeru Sharma
Uddhavesh Sonavane
Rajendra Joshi

Bioinformatics Group
Centre for Development of Advanced Computing (C-DAC)
Pune University Campus
Pune, India 411 007

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