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A graph theoretical approach to the effect of mutation on the flexibility of the DNA binding domain of p53 protein

Shah Md. Abdur Rauf, Mohamed Ismael, Kamlesh Kumar Sahu, Ai Suzuki, Riadh Sahnoun, Michihisa Koyama, Hideyuki Tsuboi, Nozomu Hatakeyama, Akira Endou, Hiromitsu Takaba, Carlos A. Del Carpio, Momoji Kubo, and Akira Miyamoto

Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan

 

E-mail: rauf_94@yahoo.com

Received: 27 February 2009  Revised: 27 May 2009  Accepted: 11 June 2009

Abstract: Tumor suppressor protein p53 becomes inactive due to mutation on its DNA binding core domain leading to misbehavior of this protein and preventing its interaction with DNA. In the present study, changes of the protein conformation by five hot spot mutations of T-p53C were assessed preventing the mutants wild-type (WT) behavior. While studies of this nature were undertaken both experimentally and theoretically, the focus is fundamentally on the effects of the mutation on the dynamics of the protein. Hence, the basic concept underlying this study is the change in flexibility or rigidity of the protein. It was found that stable variant T-p53C (PDB-ID: 1uol) that is structurally and functionally very close to wild-type p53 is the most rigid structure and each single carcinogenic mutation on it makes the structure more flexible. We hypothesize that these changes of the molecule’s flexibility disrupt the network of hydrogen bonds associated with the interaction of WT not only at interaction but in the internal structures of the mutants as well, which prevents them from interacting in the WT fashion loosing the anti-cancer properties of WT.

Keywords: effect of mutation - flexibility - p53 protein

Full paper is available at www.springerlink.com.

DOI: 10.2478/s11696-009-0068-9

 

Chemical Papers 63 (6) 654–661 (2009)

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