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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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Plot of eigenvalues corresponding to eigenvector index for the first fifty modes of motion of p53C.A) represents the apo simulation B) represents the holo simulation. Black: WT, red: R110P, green: P151T and blue: P278A.
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pone-0104242-g012: Plot of eigenvalues corresponding to eigenvector index for the first fifty modes of motion of p53C.A) represents the apo simulation B) represents the holo simulation. Black: WT, red: R110P, green: P151T and blue: P278A.

Mentions: Moreover, to identify the correlated motions of the WT and MTs during trajectory generated by apo and holo simulations and to support our MDS result we performed ED analysis. Since sum of the eigenvalues is a measure of the total motility in the system, we have plotted the eigenvalues against the corresponding eigenvector index for the first ten modes of motion at different trajectory lengths for WT and MTs during the apo and holo simulations in the Fig. 12 a, b. Only few eigenvectors showed large eigenvalues for both WT and MTs during the apo and holo simulations indicating that most of the internal motion of the protein is confined along small dimension in the essential subspace. The spectrum of eigenvalues in the Fig. 12 a,b indicated that major fluctuations of the system were confined to first two eigenvectors. Hence, the projection of trajectories of WT and MTs during the apo and holo simulations in the phase space along the first two principal components (PC1, PC2) at 300 K was plotted in the Fig. 13 a-f. Compared to apo simulation, during holo simulation MTs covered a larger region of phase space along PC1 and PC2 plane than WT. The overall flexibility of WT and MTs was calculated by the trace of the diagonalized covariance matrix of the Cα atomic positional fluctuations. Results from the trace of the covariance matrix (Table 4) confirmed the overall flexibility between MTs and WT at 300K during both apo and holo simulations. Overall the results reported from our study has confirmed that the substitution of Arginine at 110th residue with Proline, Proline at 151th residue with Threonine and Proline at 278th residue with Alanine in the p53 core domain in the presence or absence of Zn2+ has an altered structure stability and essential hydrogen bond formation and thus these three mutants might play a significant role in initiating the susceptibility towards breast cancer. Further, our analysis indicates that compared to other MTs P151T and P278A, amino acid substitution of Arginine at 110th residue with Proline (R110P) exhibit a highly deleterious effect on the p53C.


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)

Plot of eigenvalues corresponding to eigenvector index for the first fifty modes of motion of p53C.A) represents the apo simulation B) represents the holo simulation. 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-g012: Plot of eigenvalues corresponding to eigenvector index for the first fifty modes of motion of p53C.A) represents the apo simulation B) represents the holo simulation. Black: WT, red: R110P, green: P151T and blue: P278A.
Mentions: Moreover, to identify the correlated motions of the WT and MTs during trajectory generated by apo and holo simulations and to support our MDS result we performed ED analysis. Since sum of the eigenvalues is a measure of the total motility in the system, we have plotted the eigenvalues against the corresponding eigenvector index for the first ten modes of motion at different trajectory lengths for WT and MTs during the apo and holo simulations in the Fig. 12 a, b. Only few eigenvectors showed large eigenvalues for both WT and MTs during the apo and holo simulations indicating that most of the internal motion of the protein is confined along small dimension in the essential subspace. The spectrum of eigenvalues in the Fig. 12 a,b indicated that major fluctuations of the system were confined to first two eigenvectors. Hence, the projection of trajectories of WT and MTs during the apo and holo simulations in the phase space along the first two principal components (PC1, PC2) at 300 K was plotted in the Fig. 13 a-f. Compared to apo simulation, during holo simulation MTs covered a larger region of phase space along PC1 and PC2 plane than WT. The overall flexibility of WT and MTs was calculated by the trace of the diagonalized covariance matrix of the Cα atomic positional fluctuations. Results from the trace of the covariance matrix (Table 4) confirmed the overall flexibility between MTs and WT at 300K during both apo and holo simulations. Overall the results reported from our study has confirmed that the substitution of Arginine at 110th residue with Proline, Proline at 151th residue with Threonine and Proline at 278th residue with Alanine in the p53 core domain in the presence or absence of Zn2+ has an altered structure stability and essential hydrogen bond formation and thus these three mutants might play a significant role in initiating the susceptibility towards breast cancer. Further, our analysis indicates that compared to other MTs P151T and P278A, amino acid substitution of Arginine at 110th residue with Proline (R110P) exhibit a highly deleterious effect on the p53C.

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