The ability of locked nucleic acid oligonucleotides to pre-structure the double helix: A molecular simulation and binding study

You Xu, Olof Gissberg, Y Vladimir Pabon-Martinez, Jesper Wengel, Karin E Lundin, C I Edvard Smith, Rula Zain, Lennart Nilsson, Alessandra Villa

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Abstract

Locked nucleic acid (LNA) oligonucleotides bind DNA target sequences forming Watson-Crick and Hoogsteen base pairs, and are therefore of interest for medical applications. To be biologically active, such an oligonucleotide has to efficiently bind the target sequence. Here we used molecular dynamics simulations and electrophoresis mobility shift assays to elucidate the relation between helical structure and affinity for LNA-containing oligonucleotides. In particular, we have studied how LNA substitutions in the polypyrimidine strand of a duplex (thus forming a hetero duplex, i.e. a duplex with a DNA polypurine strand and an LNA/DNA polypyrimidine strand) enhance triplex formation. Based on seven polypyrimidine single strand oligonucleotides, having LNAs in different positions and quantities, we show that alternating LNA with one or more non-modified DNA nucleotides pre-organizes the hetero duplex toward a triple-helical-like conformation. This in turn promotes triplex formation, while consecutive LNAs distort the duplex structure disfavoring triplex formation. The results support the hypothesis that a pre-organization in the hetero duplex structure enhances the binding of triplex forming oligonucleotides. Our findings may serve as a criterion in the design of new tools for efficient oligonucleotide hybridization.

Original languageEnglish
Article numbere0211651
JournalPLOS ONE
Volume14
Issue number2
Number of pages14
ISSN1932-6203
DOIs
Publication statusPublished - 2019

Fingerprint

oligonucleotides
Oligonucleotides
nucleic acids
DNA
molecular dynamics
Medical applications
Electrophoretic Mobility Shift Assay
Molecular Dynamics Simulation
Electrophoresis
Base Pairing
electrophoresis
Conformations
Molecular dynamics
locked nucleic acid
Assays
Substitution reactions
hybridization
Nucleotides
nucleotides
Computer simulation

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Xu, You ; Gissberg, Olof ; Pabon-Martinez, Y Vladimir ; Wengel, Jesper ; Lundin, Karin E ; Smith, C I Edvard ; Zain, Rula ; Nilsson, Lennart ; Villa, Alessandra. / The ability of locked nucleic acid oligonucleotides to pre-structure the double helix : A molecular simulation and binding study. In: PLOS ONE. 2019 ; Vol. 14, No. 2.
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abstract = "Locked nucleic acid (LNA) oligonucleotides bind DNA target sequences forming Watson-Crick and Hoogsteen base pairs, and are therefore of interest for medical applications. To be biologically active, such an oligonucleotide has to efficiently bind the target sequence. Here we used molecular dynamics simulations and electrophoresis mobility shift assays to elucidate the relation between helical structure and affinity for LNA-containing oligonucleotides. In particular, we have studied how LNA substitutions in the polypyrimidine strand of a duplex (thus forming a hetero duplex, i.e. a duplex with a DNA polypurine strand and an LNA/DNA polypyrimidine strand) enhance triplex formation. Based on seven polypyrimidine single strand oligonucleotides, having LNAs in different positions and quantities, we show that alternating LNA with one or more non-modified DNA nucleotides pre-organizes the hetero duplex toward a triple-helical-like conformation. This in turn promotes triplex formation, while consecutive LNAs distort the duplex structure disfavoring triplex formation. The results support the hypothesis that a pre-organization in the hetero duplex structure enhances the binding of triplex forming oligonucleotides. Our findings may serve as a criterion in the design of new tools for efficient oligonucleotide hybridization.",
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Xu, Y, Gissberg, O, Pabon-Martinez, YV, Wengel, J, Lundin, KE, Smith, CIE, Zain, R, Nilsson, L & Villa, A 2019, 'The ability of locked nucleic acid oligonucleotides to pre-structure the double helix: A molecular simulation and binding study', PLOS ONE, vol. 14, no. 2, e0211651. https://doi.org/10.1371/journal.pone.0211651

The ability of locked nucleic acid oligonucleotides to pre-structure the double helix : A molecular simulation and binding study. / Xu, You; Gissberg, Olof; Pabon-Martinez, Y Vladimir; Wengel, Jesper; Lundin, Karin E; Smith, C I Edvard; Zain, Rula; Nilsson, Lennart; Villa, Alessandra.

In: PLOS ONE, Vol. 14, No. 2, e0211651, 2019.

Research output: Contribution to journalJournal articleResearchpeer-review

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T1 - The ability of locked nucleic acid oligonucleotides to pre-structure the double helix

T2 - A molecular simulation and binding study

AU - Xu, You

AU - Gissberg, Olof

AU - Pabon-Martinez, Y Vladimir

AU - Wengel, Jesper

AU - Lundin, Karin E

AU - Smith, C I Edvard

AU - Zain, Rula

AU - Nilsson, Lennart

AU - Villa, Alessandra

PY - 2019

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N2 - Locked nucleic acid (LNA) oligonucleotides bind DNA target sequences forming Watson-Crick and Hoogsteen base pairs, and are therefore of interest for medical applications. To be biologically active, such an oligonucleotide has to efficiently bind the target sequence. Here we used molecular dynamics simulations and electrophoresis mobility shift assays to elucidate the relation between helical structure and affinity for LNA-containing oligonucleotides. In particular, we have studied how LNA substitutions in the polypyrimidine strand of a duplex (thus forming a hetero duplex, i.e. a duplex with a DNA polypurine strand and an LNA/DNA polypyrimidine strand) enhance triplex formation. Based on seven polypyrimidine single strand oligonucleotides, having LNAs in different positions and quantities, we show that alternating LNA with one or more non-modified DNA nucleotides pre-organizes the hetero duplex toward a triple-helical-like conformation. This in turn promotes triplex formation, while consecutive LNAs distort the duplex structure disfavoring triplex formation. The results support the hypothesis that a pre-organization in the hetero duplex structure enhances the binding of triplex forming oligonucleotides. Our findings may serve as a criterion in the design of new tools for efficient oligonucleotide hybridization.

AB - Locked nucleic acid (LNA) oligonucleotides bind DNA target sequences forming Watson-Crick and Hoogsteen base pairs, and are therefore of interest for medical applications. To be biologically active, such an oligonucleotide has to efficiently bind the target sequence. Here we used molecular dynamics simulations and electrophoresis mobility shift assays to elucidate the relation between helical structure and affinity for LNA-containing oligonucleotides. In particular, we have studied how LNA substitutions in the polypyrimidine strand of a duplex (thus forming a hetero duplex, i.e. a duplex with a DNA polypurine strand and an LNA/DNA polypyrimidine strand) enhance triplex formation. Based on seven polypyrimidine single strand oligonucleotides, having LNAs in different positions and quantities, we show that alternating LNA with one or more non-modified DNA nucleotides pre-organizes the hetero duplex toward a triple-helical-like conformation. This in turn promotes triplex formation, while consecutive LNAs distort the duplex structure disfavoring triplex formation. The results support the hypothesis that a pre-organization in the hetero duplex structure enhances the binding of triplex forming oligonucleotides. Our findings may serve as a criterion in the design of new tools for efficient oligonucleotide hybridization.

U2 - 10.1371/journal.pone.0211651

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