The effect of R249S carcinogenic and H168R-R249S suppressor mutations on p53-DNA interaction, a multi scale computational study

  • Authors:

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

  • Affiliations:

  • Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;NICHe, Tohoku University, 6-6-10 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;INAMORI Frontier Research Center, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan;FRI, Graduate School of Engineering, Tohoku University, 6-6-11-701 Aoba, Aramaki, Aoba-ku, Sendai 980-579, Japan;Graduate School of Engineering, Tohoku University, 6-6-11-1302 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan and NICHe, Tohoku University, 6-6-10 Aoba, Aramaki, Aoba-ku, Sendai 980-8579, Japan

  • Venue:
  • Computers in Biology and Medicine
  • Year:
  • 2010

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Abstract

In this study we have undertaken the theoretical analysis of the effect of R249S carcinogenic and H168R-R249S suppressor mutation at core domain of the tumor suppressor protein p53, on its natural interaction with DNA using a newly developed method. The results show that the carcinogenic mutation R249S affects the flexibility of L3 loop region in p53, inducing the loss of important hydrogen bonds observed at interaction in the wild-type with DNA, on the other hand the suppressor mutation H168R on the R249S assists in maintaining the wild-type like flexibility of the L3 region in p53 and thus recover the interaction terms lost in the carcinogenic mutation alone. The present study sets a new direction in the development of new drugs that may restore the interactions that lost as a consequence of the carcinogenic mutations in p53.