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Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA
The predictable 3D structure of double-stranded DNA renders it ideally suited as a template for the bottom-up design of functionalized nucleic acid-based active sites. We here explore the use of a 14mer DNA duplex as a scaffold for the precise and predictable positioning of catalytic functionalities...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288195/ https://www.ncbi.nlm.nih.gov/pubmed/25520197 http://dx.doi.org/10.1093/nar/gku1306 |
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author | Buyst, Dieter Gheerardijn, Vicky Fehér, Krisztina Van Gasse, Bjorn Van Den Begin, Jos Martins, José C. Madder, Annemieke |
author_facet | Buyst, Dieter Gheerardijn, Vicky Fehér, Krisztina Van Gasse, Bjorn Van Den Begin, Jos Martins, José C. Madder, Annemieke |
author_sort | Buyst, Dieter |
collection | PubMed |
description | The predictable 3D structure of double-stranded DNA renders it ideally suited as a template for the bottom-up design of functionalized nucleic acid-based active sites. We here explore the use of a 14mer DNA duplex as a scaffold for the precise and predictable positioning of catalytic functionalities. Given the ubiquitous participation of the histidine-based imidazole group in protein recognition and catalysis events, single histidine-like modified duplexes were investigated. Tethering histamine to the C5 of the thymine base via an amide bond, allows the flexible positioning of the imidazole function in the major groove. The mutual interactions between the imidazole and the duplex and its influence on the imidazolium pKa(H) are investigated by placing a single modified thymine at four different positions in the center of the 14mer double helix. Using NMR and unrestrained molecular dynamics, a structural motif involving the formation of a hydrogen bond between the imidazole and the Hoogsteen side of the guanine bases of two neighboring GC base pairs is established. The motif contributes to a stabilization against thermal melting of 6°C and is key in modulating the pKa(H) of the imidazolium group. The general features, prerequisites and generic character of the new pKa(H)-regulating motif are described. |
format | Online Article Text |
id | pubmed-4288195 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-42881952015-02-19 Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA Buyst, Dieter Gheerardijn, Vicky Fehér, Krisztina Van Gasse, Bjorn Van Den Begin, Jos Martins, José C. Madder, Annemieke Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry The predictable 3D structure of double-stranded DNA renders it ideally suited as a template for the bottom-up design of functionalized nucleic acid-based active sites. We here explore the use of a 14mer DNA duplex as a scaffold for the precise and predictable positioning of catalytic functionalities. Given the ubiquitous participation of the histidine-based imidazole group in protein recognition and catalysis events, single histidine-like modified duplexes were investigated. Tethering histamine to the C5 of the thymine base via an amide bond, allows the flexible positioning of the imidazole function in the major groove. The mutual interactions between the imidazole and the duplex and its influence on the imidazolium pKa(H) are investigated by placing a single modified thymine at four different positions in the center of the 14mer double helix. Using NMR and unrestrained molecular dynamics, a structural motif involving the formation of a hydrogen bond between the imidazole and the Hoogsteen side of the guanine bases of two neighboring GC base pairs is established. The motif contributes to a stabilization against thermal melting of 6°C and is key in modulating the pKa(H) of the imidazolium group. The general features, prerequisites and generic character of the new pKa(H)-regulating motif are described. Oxford University Press 2015-01-09 2014-12-17 /pmc/articles/PMC4288195/ /pubmed/25520197 http://dx.doi.org/10.1093/nar/gku1306 Text en © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Buyst, Dieter Gheerardijn, Vicky Fehér, Krisztina Van Gasse, Bjorn Van Den Begin, Jos Martins, José C. Madder, Annemieke Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA |
title | Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA |
title_full | Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA |
title_fullStr | Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA |
title_full_unstemmed | Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA |
title_short | Identification of a pKa-regulating motif stabilizing imidazole-modified double-stranded DNA |
title_sort | identification of a pka-regulating motif stabilizing imidazole-modified double-stranded dna |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4288195/ https://www.ncbi.nlm.nih.gov/pubmed/25520197 http://dx.doi.org/10.1093/nar/gku1306 |
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