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Acta Physico-Chimica Sinca  2016, Vol. 32 Issue (10): 2620-2627    DOI: 10.3866/PKU.WHXB201606224
ARTICLE     
Effect of Y220C Mutant on the Conformational Transition of p53C Probed by Molecular Dynamics Simulation
Hong-Chen SHEN1,Ji-Yong DING1,Li LI2,Fu-Feng LIU1,3,*()
1 Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China
2 College of Marine and Environmental Sciences, Tianjin University of Science & Technology, Tianjin 300457
3 College of Biotechnology, Tianjin University of Science & Technology, Tianjin 300457, P. R. China
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Abstract  

At present, p53 is the tumor suppressor protein with the highest known frequency of mutation. Mutations in p53 will lead to the loss of its anti-cancer function and initiate cancers. The majority of the mutations in p53 are located in its core DNA binding domain (p53C). One of the most frequent mutation in p53C is Y220C. However, the molecular mechanism of the conformational transition of the Y220C mutant of p53C remains unclear, although it is known that the Y220C mutant greatly decreases the stability of p53C. In this study, molecular dynamics (MD) simulations are used to probe the conformational transition of the Y220C mutant of p53C. The Y220C cluster including residues 138-164 and 215-238, which are strongly affected by the mutant, is identified. The Y220C mutant decreases the content of β-sheets in the Y220C cluster. The Y220C mutation not only disrupts the hydrogen bonds between the mutated residue and surrounding residues such as Leu145 and Thr155, but also weakens the hydrogen bonds between S3 and S8 of the Y220C cluster. This causes the volume of the hydrophilic cavity to increase, accelerating water molecule entry into the cavity, which eventually unfolds the protein. The above MD results explain the molecular mechanism of the Y220C mutant in the conformational transition of p53C. These findings will benefit virtual screening and design of novel stabilizers of the mutant Y220C of p53C.



Key wordsCancer      p53      Residue mutation      Conformational transition      Molecular dynamics simulation     
Received: 06 April 2016      Published: 22 June 2016
MSC2000:  O641  
Fund:  the National Natural Science Foundation of China(21576199)
Corresponding Authors: Fu-Feng LIU     E-mail: fufengliu@tju.edu.cn
Cite this article:

Hong-Chen SHEN,Ji-Yong DING,Li LI,Fu-Feng LIU. Effect of Y220C Mutant on the Conformational Transition of p53C Probed by Molecular Dynamics Simulation. Acta Physico-Chimica Sinca, 2016, 32(10): 2620-2627.

URL:

http://www.whxb.pku.edu.cn/10.3866/PKU.WHXB201606224     OR     http://www.whxb.pku.edu.cn/Y2016/V32/I10/2620

Fig 1  3D structure of p53C-Y220C (a) Secondary structure of p53C-Y220C is shown by the NewCartoon model. β-sheet, helix, and loop are represented by S, H and L, respectively. (b) p53C-Y220C and Cys220 are shown as the VDW and Surf models, respectively. The snapshot is plotted with the visual molecular dynamics (VMD) software (http://www.ks.uiuc.edu/Research/vmd/).
Fig 2  Root-mean-square deviations (RMSD) for Cα atoms of p53C and p53-Y220C as a function of time for the simulations
Fig 3  Root mean square fluctuation (RMSF) for Cα atom per residue for p53C and p53C-Y220C during the MD simulations
Fig 4  RMSD for Cα atom of Y220C cluster of p53C and p53C-Y220C as a function of time for the simulations
Fig 5  Secondary structure of Y220C cluster as a function of simulation time for p53C (a) and p53C-Y220C (b) The vertical coordinate represents the residue number, and the secondary structures coded as given in the bottom of the figure.
Secondaryp53Cp53C-Y220C
structure0 ns100 ns0 ns100 ns
coil44.9%38.7%42.9%49%
β-sheet40.8%42.9%40.8%32.7%
β-bridge0%0%0%4.1%
bend10.2%12.2%8.2%10.2%
turn4.1%6.1%8.2%4.1%
Table 1  Content of secondary structures of Y220C cluster in p53C and p53C-Y220C
Fig 6  Hydrogen bonds interaction of Tyr220 with surrounding residues in p53C (a) and Cys220 with surrounding residues in p53C-Y220C (b) in the 100 ns MD simulations The presence of H-bond interactions at any time is represented by mark. The stable H-bonds are emphasized with black arrows.
Fig 7  Hydrogen bond analyses of Tyr220 with surrounding residues in p53C (a) and Cys220 with surrounding residues in p53C-Y220C (b) Hydrogen bonds are shown as black dashed lines. The main chains ofthe S3 and S8 are shown by a yellow NewCartoon model. Residues Leu145, Thr155, Tyr220, and Cys220 are shown in a Licorice model. Atoms of these residues are colored red for oxygen, white for hydrogen, blue for nitrogen, green for carbon, and yellow for sulfur (color online).
Fig 8  Numbers of H-bonds between S3 and S8 of p53C and p53C-Y220C as functions of simulation time
Fig 9  Scheme of hydrogen bonds between backbones of S3 and S8 for p53C and p53C-Y220C during the 100 ns MD simulation The illustrations of the snapshots are the same as those described in the caption to Fig. 7.
Fig 10  Values of hydrophilic and hydrophobic solvent accessible surface area (SASA) of Y220C cluster as a function of simulation time for p53C and p53C-Y220C during the 100 ns MD simulation
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