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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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Number density plot of p53C.A) Apo WT B) Apo R110P C) Apo P151T D) Apo P278A E) Holo WT F) Holo R110P G) Holo P151T F) Holo P278A.
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pone-0104242-g011: Number density plot of p53C.A) Apo WT B) Apo R110P C) Apo P151T D) Apo P278A E) Holo WT F) Holo R110P G) Holo P151T F) Holo P278A.

Mentions: Further, one of the factors that accounts for maintaining the stable conformation of a protein is hydrogen bonding. In order to understand the reason for flexibility among the MTs we have performed the NH bond analysis of WT and MTs during apo and holo simulations and plotted in the Fig. 10a-f. Results showed a notable difference in protein-solvent intermolecular hydrogen bond pattern between the WT and MTs. Among the MTs, a decrease in the average number of hydrogen bonds was observed in R110P compared to the WT during both apo and holo simulations (Fig. 10a,d) indicting that the occurrence of this mutation may lead to a more flexible conformation in the presence or absence of Zn2+ at physiological conditions. However, the other MTs, P151T and P278A showed a decrease in average number of protein-solvent intermolecular hydrogen bonds only during holo simulations (Fig. 10e,f) indicating that these two mutants are flexible only in the presence of Zn2+ at physiological conditions. Further, we have plotted the atom density distribution to check if the MTs have caused any major changes in the orientation and atomic distribution. Results showed that atomic distribution of all the MTs were significantly differed from the WT in apo and holo simulations (Fig. 11a-h) indicating that all the MTs have a 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)

Number density plot of p53C.A) Apo WT B) Apo R110P C) Apo P151T D) Apo P278A E) Holo WT F) Holo R110P G) Holo P151T F) Holo P278A.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104242-g011: Number density plot of p53C.A) Apo WT B) Apo R110P C) Apo P151T D) Apo P278A E) Holo WT F) Holo R110P G) Holo P151T F) Holo P278A.
Mentions: Further, one of the factors that accounts for maintaining the stable conformation of a protein is hydrogen bonding. In order to understand the reason for flexibility among the MTs we have performed the NH bond analysis of WT and MTs during apo and holo simulations and plotted in the Fig. 10a-f. Results showed a notable difference in protein-solvent intermolecular hydrogen bond pattern between the WT and MTs. Among the MTs, a decrease in the average number of hydrogen bonds was observed in R110P compared to the WT during both apo and holo simulations (Fig. 10a,d) indicting that the occurrence of this mutation may lead to a more flexible conformation in the presence or absence of Zn2+ at physiological conditions. However, the other MTs, P151T and P278A showed a decrease in average number of protein-solvent intermolecular hydrogen bonds only during holo simulations (Fig. 10e,f) indicating that these two mutants are flexible only in the presence of Zn2+ at physiological conditions. Further, we have plotted the atom density distribution to check if the MTs have caused any major changes in the orientation and atomic distribution. Results showed that atomic distribution of all the MTs were significantly differed from the WT in apo and holo simulations (Fig. 11a-h) indicating that all the MTs have a 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