Modulation of the Disordered Conformational Ensembles of the p53 Transactivation Domain by Cancer-Associated Mutations

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dc.contributor.author Ganguly, D.
dc.contributor.author Chen, Jianhan H.
dc.date.accessioned 2016-03-28T19:20:17Z
dc.date.available 2016-03-28T19:20:17Z
dc.identifier.uri http://hdl.handle.net/2097/32202
dc.description Citation: Ganguly, D., & Chen, J. H. (2015). Modulation of the Disordered Conformational Ensembles of the p53 Transactivation Domain by Cancer-Associated Mutations. Plos Computational Biology, 11(4), 19. doi:10.1371/journal.pcbi.1004247
dc.description Intrinsically disordered proteins (IDPs) are frequently associated with human diseases such as cancers, and about one-fourth of disease-associated missense mutations have been mapped into predicted disordered regions. Understanding how these mutations affect the structure-function relationship of IDPs is a formidable task that requires detailed characterization of the disordered conformational ensembles. Implicit solvent coupled with enhanced sampling has been proposed to provide a balance between accuracy and efficiency necessary for systematic and comparative assessments of the effects of mutations as well as post-translational modifications on IDP structure and interaction. Here, we utilize a recently developed replica exchange with guided annealing enhanced sampling technique to calculate well-converged atomistic conformational ensembles of the intrinsically disordered transactivation domain (TAD) of tumor suppressor p53 and several cancer-associated mutants in implicit solvent. The simulations are critically assessed by quantitative comparisons with several types of experimental data that provide structural information on both secondary and tertiary levels. The results show that the calculated ensembles reproduce local structural features of wild-type p53-TAD and the effects of K24N mutation quantitatively. On the tertiary level, the simulated ensembles are overly compact, even though they appear to recapitulate the overall features of transient long-range contacts qualitatively. A key finding is that, while p53-TAD and its cancer mutants sample a similar set of conformational states, cancer mutants could introduce both local and long-range structural modulations to potentially perturb the balance of p53 binding to various regulatory proteins and further alter how this balance is regulated by multisite phosphorylation of p53-TAD. The current study clearly demonstrates the promise of atomistic simulations for detailed characterization of IDP conformations, and at the same time reveals important limitations in the current implicit solvent protein force field that must be sufficiently addressed for reliable description of long-range structural features of the disordered ensembles.
dc.relation.uri https://doi.org/10.1371/journal.pcbi.1004247
dc.rights Attribution 4.0 International (CC BY 4.0)
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject Long-Range Structure
dc.subject Paramagnetic Relaxation Enhancement
dc.subject Molecular-Dynamics Simulations
dc.subject Creb-Binding-Protein
dc.subject Tumor-Suppressor
dc.subject P53
dc.title Modulation of the Disordered Conformational Ensembles of the p53 Transactivation Domain by Cancer-Associated Mutations
dc.type Article
dc.date.published 2015
dc.citation.doi 10.1371/journal.pcbi.1004247
dc.citation.issn 1553-734X
dc.citation.issue 4
dc.citation.jtitle PLoS Computational Biology
dc.citation.spage 19
dc.citation.volume 11
dc.contributor.authoreid jianhanc


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