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Ion-Dependent Conformational Plasticity of Telomeric G-Hairpins and G-Quadruplexes
[Image: see text] Telomeric DNA is guanine-rich and can adopt structures such as G-quadruplexes (GQs) and G-hairpins. Telomeric GQs influence genome stability and telomerase activity, making understanding of enzyme–GQ interactions and dynamics important for potential drug design. GQs have a characte...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280957/ https://www.ncbi.nlm.nih.gov/pubmed/35847338 http://dx.doi.org/10.1021/acsomega.2c01600 |
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author | Salsbury, Alexa M. Michel, Haley M. Lemkul, Justin A. |
author_facet | Salsbury, Alexa M. Michel, Haley M. Lemkul, Justin A. |
author_sort | Salsbury, Alexa M. |
collection | PubMed |
description | [Image: see text] Telomeric DNA is guanine-rich and can adopt structures such as G-quadruplexes (GQs) and G-hairpins. Telomeric GQs influence genome stability and telomerase activity, making understanding of enzyme–GQ interactions and dynamics important for potential drug design. GQs have a characteristic tetrad core, which is connected by loop regions. Within this architecture are G-hairpins, fold-back motifs that are thought to represent the first intermediate in GQ folding. To better understand the relationship between G-hairpin motifs and GQs, we performed polarizable simulations of a two-tetrad telomeric GQ and an isolated SC11 telomeric G-hairpin. The telomeric GQ contains a G-triad, which functions as part of the tetrad core or linker regions, depending on local conformational change. This triad and another motif below the tetrad core frequently bound ions and may represent druggable sites. Further, we observed the unbiased formation of a G-triad and a G-tetrad in simulations of the SC11 G-hairpin and found that cations can be partially hydrated while facilitating the formation of these motifs. Finally, we demonstrated that K(+) ions form specific interactions with guanine bases, while Na(+) ions interact nonspecifically with bases in the structure. Together, these simulations provide new insights into the influence of ions on GQs, G-hairpins, and G-triad motifs. |
format | Online Article Text |
id | pubmed-9280957 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-92809572022-07-15 Ion-Dependent Conformational Plasticity of Telomeric G-Hairpins and G-Quadruplexes Salsbury, Alexa M. Michel, Haley M. Lemkul, Justin A. ACS Omega [Image: see text] Telomeric DNA is guanine-rich and can adopt structures such as G-quadruplexes (GQs) and G-hairpins. Telomeric GQs influence genome stability and telomerase activity, making understanding of enzyme–GQ interactions and dynamics important for potential drug design. GQs have a characteristic tetrad core, which is connected by loop regions. Within this architecture are G-hairpins, fold-back motifs that are thought to represent the first intermediate in GQ folding. To better understand the relationship between G-hairpin motifs and GQs, we performed polarizable simulations of a two-tetrad telomeric GQ and an isolated SC11 telomeric G-hairpin. The telomeric GQ contains a G-triad, which functions as part of the tetrad core or linker regions, depending on local conformational change. This triad and another motif below the tetrad core frequently bound ions and may represent druggable sites. Further, we observed the unbiased formation of a G-triad and a G-tetrad in simulations of the SC11 G-hairpin and found that cations can be partially hydrated while facilitating the formation of these motifs. Finally, we demonstrated that K(+) ions form specific interactions with guanine bases, while Na(+) ions interact nonspecifically with bases in the structure. Together, these simulations provide new insights into the influence of ions on GQs, G-hairpins, and G-triad motifs. American Chemical Society 2022-06-29 /pmc/articles/PMC9280957/ /pubmed/35847338 http://dx.doi.org/10.1021/acsomega.2c01600 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Salsbury, Alexa M. Michel, Haley M. Lemkul, Justin A. Ion-Dependent Conformational Plasticity of Telomeric G-Hairpins and G-Quadruplexes |
title | Ion-Dependent Conformational Plasticity of Telomeric
G-Hairpins and G-Quadruplexes |
title_full | Ion-Dependent Conformational Plasticity of Telomeric
G-Hairpins and G-Quadruplexes |
title_fullStr | Ion-Dependent Conformational Plasticity of Telomeric
G-Hairpins and G-Quadruplexes |
title_full_unstemmed | Ion-Dependent Conformational Plasticity of Telomeric
G-Hairpins and G-Quadruplexes |
title_short | Ion-Dependent Conformational Plasticity of Telomeric
G-Hairpins and G-Quadruplexes |
title_sort | ion-dependent conformational plasticity of telomeric
g-hairpins and g-quadruplexes |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9280957/ https://www.ncbi.nlm.nih.gov/pubmed/35847338 http://dx.doi.org/10.1021/acsomega.2c01600 |
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