Open AccessThe ability of locked nucleic acid oligonucleotides to pre-structure the double helix: A molecular simulation and binding study
Author(s) -
You Xu,
Olof Gissberg,
Y. Vladimir Pabón-Martínez,
Jesper Wengel,
Karin E. Lundin,
C. I. Edvard Smith,
Rula Zain,
Lennart Nilsson,
Alessandra Villa
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0211651
Subject(s) - oligonucleotide , triple helix , duplex (building) , locked nucleic acid , nucleic acid , dna , nucleotide , nucleic acid thermodynamics , nucleic acid structure , base pair , nucleic acid sequence , helix (gastropod) , biophysics , chemistry , biology , biochemistry , microbiology and biotechnology , rna , stereochemistry , base sequence , gene , ecology , snail
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.