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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...

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Autores principales: Buyst, Dieter, Gheerardijn, Vicky, Fehér, Krisztina, Van Gasse, Bjorn, Van Den Begin, Jos, Martins, José C., Madder, Annemieke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
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.
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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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