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Stability of the core domain of p53: insights from computer simulations

BACKGROUND: The tumour suppressor protein p53 protein has a core domain that binds DNA and is the site for most oncogenic mutations. This domain is quite unstable compared to its homologs p63 and p73. Two key residues in the core domain of p53 (Tyr236, Thr253), have been mutated in-silico, to their...

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Autores principales: Madhumalar, Arumugam, Smith, Derek John, Verma, Chandra
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2259418/
https://www.ncbi.nlm.nih.gov/pubmed/18315848
http://dx.doi.org/10.1186/1471-2105-9-S1-S17
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author Madhumalar, Arumugam
Smith, Derek John
Verma, Chandra
author_facet Madhumalar, Arumugam
Smith, Derek John
Verma, Chandra
author_sort Madhumalar, Arumugam
collection PubMed
description BACKGROUND: The tumour suppressor protein p53 protein has a core domain that binds DNA and is the site for most oncogenic mutations. This domain is quite unstable compared to its homologs p63 and p73. Two key residues in the core domain of p53 (Tyr236, Thr253), have been mutated in-silico, to their equivalent residues in p63 (Phe238 and Ile255) and p73 (Phe238 and Ile255), with subsequent increase in stability of p53. Computational studies have been performed to examine the basis of instability in p53. RESULTS: Molecular dynamics simulations suggest that mutations in p53 lead to increased conformational sampling of the phase space which stabilizes the system entropically. In contrast, reverse mutations, where p63 and p73 were mutated by replacing the Phe238 and Ile255 by Tyr and Thr respectively (as in p53), showed reduced conformational sampling although the change for p63 was much smaller than that for p73. Barriers to the rotation of sidechains containing aromatic rings at the core of the proteins were reduced several-fold when p53 was mutated; in contrast they increased when p73 was mutated and decreased by a small amount in p63. The rate of ring flipping of a Tyrosine residue at the boundary of two domains can be correlated with the change in stability, with implications for possible pathways of entry of agents that induce unfolding. CONCLUSION: A double mutation at the core of the DNA binding domain of p53 leads to enhanced stability by increasing the softness of the protein. A change from a highly directional polar interaction of the core residues Tyr236 and Thr253 to a non-directional apolar interaction between Phe and Ile respectively may enable the system to adapt more easily and thus increase its robustness to structural perturbations, giving it increased stability. This leads to enhanced conformational sampling which in turn is associated with an increased "softness" of the protein core. However the system seems to become more rigid at the periphery. The success of this methodology in reproducing the experimental trends in the stability of p53 suggests that it has the potential to complement structural studies for rapidly estimating changes in stability upon mutations and could be an additional tool in the design of specific classes of proteins.
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spelling pubmed-22594182008-03-04 Stability of the core domain of p53: insights from computer simulations Madhumalar, Arumugam Smith, Derek John Verma, Chandra BMC Bioinformatics Proceedings BACKGROUND: The tumour suppressor protein p53 protein has a core domain that binds DNA and is the site for most oncogenic mutations. This domain is quite unstable compared to its homologs p63 and p73. Two key residues in the core domain of p53 (Tyr236, Thr253), have been mutated in-silico, to their equivalent residues in p63 (Phe238 and Ile255) and p73 (Phe238 and Ile255), with subsequent increase in stability of p53. Computational studies have been performed to examine the basis of instability in p53. RESULTS: Molecular dynamics simulations suggest that mutations in p53 lead to increased conformational sampling of the phase space which stabilizes the system entropically. In contrast, reverse mutations, where p63 and p73 were mutated by replacing the Phe238 and Ile255 by Tyr and Thr respectively (as in p53), showed reduced conformational sampling although the change for p63 was much smaller than that for p73. Barriers to the rotation of sidechains containing aromatic rings at the core of the proteins were reduced several-fold when p53 was mutated; in contrast they increased when p73 was mutated and decreased by a small amount in p63. The rate of ring flipping of a Tyrosine residue at the boundary of two domains can be correlated with the change in stability, with implications for possible pathways of entry of agents that induce unfolding. CONCLUSION: A double mutation at the core of the DNA binding domain of p53 leads to enhanced stability by increasing the softness of the protein. A change from a highly directional polar interaction of the core residues Tyr236 and Thr253 to a non-directional apolar interaction between Phe and Ile respectively may enable the system to adapt more easily and thus increase its robustness to structural perturbations, giving it increased stability. This leads to enhanced conformational sampling which in turn is associated with an increased "softness" of the protein core. However the system seems to become more rigid at the periphery. The success of this methodology in reproducing the experimental trends in the stability of p53 suggests that it has the potential to complement structural studies for rapidly estimating changes in stability upon mutations and could be an additional tool in the design of specific classes of proteins. BioMed Central 2008-02-13 /pmc/articles/PMC2259418/ /pubmed/18315848 http://dx.doi.org/10.1186/1471-2105-9-S1-S17 Text en Copyright © 2008 Madhumalar et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an open access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Proceedings
Madhumalar, Arumugam
Smith, Derek John
Verma, Chandra
Stability of the core domain of p53: insights from computer simulations
title Stability of the core domain of p53: insights from computer simulations
title_full Stability of the core domain of p53: insights from computer simulations
title_fullStr Stability of the core domain of p53: insights from computer simulations
title_full_unstemmed Stability of the core domain of p53: insights from computer simulations
title_short Stability of the core domain of p53: insights from computer simulations
title_sort stability of the core domain of p53: insights from computer simulations
topic Proceedings
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2259418/
https://www.ncbi.nlm.nih.gov/pubmed/18315848
http://dx.doi.org/10.1186/1471-2105-9-S1-S17
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