Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions.
Transcriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relation...
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Public Library of Science (PLoS)
2016-05-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1004935&type=printable |
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| author | Natalie S Scholes Robert O J Weinzierl |
| author_facet | Natalie S Scholes Robert O J Weinzierl |
| author_sort | Natalie S Scholes |
| collection | DOAJ |
| description | Transcriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relationships of such contacts. Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 AD and variants thereof, either free in solution, or bound to the GAL11 coactivator surface. We show that the AD-coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points. We also demonstrate that a prediction of α-helical propensity correlates directly with the experimentally measured transactivation potential of a large set of mutagenized ADs. The link between α-helical propensity and the stimulatory activity of ADs has fundamental practical and theoretical implications concerning the recruitment of ADs to coactivators. |
| format | Article |
| id | doaj-art-8c416b49fbd64c4b83f874c19d3272a9 |
| institution | Kabale University |
| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2016-05-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj-art-8c416b49fbd64c4b83f874c19d3272a92025-08-20T03:24:36ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582016-05-01125e100493510.1371/journal.pcbi.1004935Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions.Natalie S ScholesRobert O J WeinzierlTranscriptional activation domains (ADs) are generally thought to be intrinsically unstructured, but capable of adopting limited secondary structure upon interaction with a coactivator surface. The indeterminate nature of this interface made it hitherto difficult to study structure/function relationships of such contacts. Here we used atomistic accelerated molecular dynamics (aMD) simulations to study the conformational changes of the GCN4 AD and variants thereof, either free in solution, or bound to the GAL11 coactivator surface. We show that the AD-coactivator interactions are highly dynamic while obeying distinct rules. The data provide insights into the constant and variable aspects of orientation of ADs relative to the coactivator, changes in secondary structure and energetic contributions stabilizing the various conformers at different time points. We also demonstrate that a prediction of α-helical propensity correlates directly with the experimentally measured transactivation potential of a large set of mutagenized ADs. The link between α-helical propensity and the stimulatory activity of ADs has fundamental practical and theoretical implications concerning the recruitment of ADs to coactivators.https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1004935&type=printable |
| spellingShingle | Natalie S Scholes Robert O J Weinzierl Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions. PLoS Computational Biology |
| title | Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions. |
| title_full | Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions. |
| title_fullStr | Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions. |
| title_full_unstemmed | Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions. |
| title_short | Molecular Dynamics of "Fuzzy" Transcriptional Activator-Coactivator Interactions. |
| title_sort | molecular dynamics of fuzzy transcriptional activator coactivator interactions |
| url | https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1004935&type=printable |
| work_keys_str_mv | AT nataliesscholes moleculardynamicsoffuzzytranscriptionalactivatorcoactivatorinteractions AT robertojweinzierl moleculardynamicsoffuzzytranscriptionalactivatorcoactivatorinteractions |