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Computational screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53 gene.

Chitrala KN, Yeguvapalli S - PLoS ONE (2014)

Bottom Line: Among them, TP53 is one of the major genetic risk factor which is known to be mutated in many of the breast tumor types.We have predicted three deleterious coding non-synonymous single nucleotide polymorphisms rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 with a phenotype in breast tumors using computational tools SIFT, Polyphen-2 and MutDB.We have performed molecular dynamics simulations to study the structural and dynamic effects of these TP53 mutations in comparison to the wild-type protein.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, Sri Venkateswara University, Tirupati, Andhra Pradesh, India.

ABSTRACT
Breast cancer is one of the most common cancers among the women around the world. Several genes are known to be responsible for conferring the susceptibility to breast cancer. Among them, TP53 is one of the major genetic risk factor which is known to be mutated in many of the breast tumor types. TP53 mutations in breast cancer are known to be related to a poor prognosis and chemo resistance. This renders them as a promising molecular target for the treatment of breast cancer. In this study, we present a computational based screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53. We have predicted three deleterious coding non-synonymous single nucleotide polymorphisms rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 with a phenotype in breast tumors using computational tools SIFT, Polyphen-2 and MutDB. We have performed molecular dynamics simulations to study the structural and dynamic effects of these TP53 mutations in comparison to the wild-type protein. Results from our simulations revealed a detailed consequence of the mutations on the p53 DNA-binding core domain that may provide insight for therapeutic approaches in breast cancer.

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Related in: MedlinePlus

Backbone rmsd values for WT, R110P, P151T and P278A during A) Apo simulations B) Holo simulations for p53C.Black: WT, red: R110P, green: P151T and blue: P278A.
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pone-0104242-g003: Backbone rmsd values for WT, R110P, P151T and P278A during A) Apo simulations B) Holo simulations for p53C.Black: WT, red: R110P, green: P151T and blue: P278A.

Mentions: Results from the calculations of RMSD for backbone and Cα atoms, root mean square fluctuation (RMSF) for Cα atoms, radius of gyration (Rg) for Cα atoms and protein for apo and holo WT, R110P, P151T, P278A MDS were presented in the Table 4. To analyze the impact of MTs on the p53C, we have examined the RMSD values. The calculated RMSDs of the backbone atoms in apo and holo WT, R110P, P151T, P278A with respect to the starting structure during the 10-ns MDS as a function of time were plotted in the Fig. 3a, b. During the apo simulations, backbone RMSDs of the WT and MT structures showed a sharp increase in the first 3 ns followed by equilibrium around 6 ns and a sudden decrease around 7.5 ns for P151T, 9.5 ns for P278A and R110P (Fig. 3a) whereas in the case of holo simulations a different pattern was observed. A sharp increase is shown during the first 3.5 ns followed by equilibrium around 4 ns and a sudden increase around 7.5 ns for P151T, P278A and a sudden decrease around 9.5 ns for R110P. A comparison of average backbone RMSD values showed the following order of structural deviations (Table 4): apo; R110P > WT > P151T  =  P278A, holo; R110P  =  P278A > WT >P151T. A variation in the average backbone RMSD values of WT and MTs lead to the conclusion that these mutations could affect the dynamic behavior of p53C, thus provides a suitable basis for further analyses.


Computational screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53 gene.

Chitrala KN, Yeguvapalli S - PLoS ONE (2014)

Backbone rmsd values for WT, R110P, P151T and P278A during A) Apo simulations B) Holo simulations for p53C.Black: WT, red: R110P, green: P151T and blue: P278A.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126775&req=5

pone-0104242-g003: Backbone rmsd values for WT, R110P, P151T and P278A during A) Apo simulations B) Holo simulations for p53C.Black: WT, red: R110P, green: P151T and blue: P278A.
Mentions: Results from the calculations of RMSD for backbone and Cα atoms, root mean square fluctuation (RMSF) for Cα atoms, radius of gyration (Rg) for Cα atoms and protein for apo and holo WT, R110P, P151T, P278A MDS were presented in the Table 4. To analyze the impact of MTs on the p53C, we have examined the RMSD values. The calculated RMSDs of the backbone atoms in apo and holo WT, R110P, P151T, P278A with respect to the starting structure during the 10-ns MDS as a function of time were plotted in the Fig. 3a, b. During the apo simulations, backbone RMSDs of the WT and MT structures showed a sharp increase in the first 3 ns followed by equilibrium around 6 ns and a sudden decrease around 7.5 ns for P151T, 9.5 ns for P278A and R110P (Fig. 3a) whereas in the case of holo simulations a different pattern was observed. A sharp increase is shown during the first 3.5 ns followed by equilibrium around 4 ns and a sudden increase around 7.5 ns for P151T, P278A and a sudden decrease around 9.5 ns for R110P. A comparison of average backbone RMSD values showed the following order of structural deviations (Table 4): apo; R110P > WT > P151T  =  P278A, holo; R110P  =  P278A > WT >P151T. A variation in the average backbone RMSD values of WT and MTs lead to the conclusion that these mutations could affect the dynamic behavior of p53C, thus provides a suitable basis for further analyses.

Bottom Line: Among them, TP53 is one of the major genetic risk factor which is known to be mutated in many of the breast tumor types.We have predicted three deleterious coding non-synonymous single nucleotide polymorphisms rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 with a phenotype in breast tumors using computational tools SIFT, Polyphen-2 and MutDB.We have performed molecular dynamics simulations to study the structural and dynamic effects of these TP53 mutations in comparison to the wild-type protein.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, Sri Venkateswara University, Tirupati, Andhra Pradesh, India.

ABSTRACT
Breast cancer is one of the most common cancers among the women around the world. Several genes are known to be responsible for conferring the susceptibility to breast cancer. Among them, TP53 is one of the major genetic risk factor which is known to be mutated in many of the breast tumor types. TP53 mutations in breast cancer are known to be related to a poor prognosis and chemo resistance. This renders them as a promising molecular target for the treatment of breast cancer. In this study, we present a computational based screening and molecular dynamic simulation of breast cancer associated deleterious non-synonymous single nucleotide polymorphisms in TP53. We have predicted three deleterious coding non-synonymous single nucleotide polymorphisms rs11540654 (R110P), rs17849781 (P278A) and rs28934874 (P151T) in TP53 with a phenotype in breast tumors using computational tools SIFT, Polyphen-2 and MutDB. We have performed molecular dynamics simulations to study the structural and dynamic effects of these TP53 mutations in comparison to the wild-type protein. Results from our simulations revealed a detailed consequence of the mutations on the p53 DNA-binding core domain that may provide insight for therapeutic approaches in breast cancer.

Show MeSH
Related in: MedlinePlus