Structures, dynamics, and stabilities of fully modified locked nucleic acid (β-D-LNA and α-L-LNA) duplexes in comparison to pure DNA and RNA duplexes

Suresh Gorle, U. Deva Priyakumar

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18 Citations (Scopus)

Abstract

Locked nucleic acid (LNA) is a chemical modification which introduces a-O-CH2-linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state. Two types of modifications, namely, 2′-O,4′-C-methylene-β-d-ribofuranose (β-d-LNA) and 2′-O,4′-C-methylene-α-l-ribofuranose (α-l-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively. LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy. In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties. Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes. Though the α-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures. Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments. π-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution. A combination of two factors, namely, nature of the-O-CH2-linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and α-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties.

Original languageEnglish (US)
Pages (from-to)5556-5564
Number of pages9
JournalJournal of Physical Chemistry B
Volume117
Issue number18
DOIs
StatePublished - May 9 2013
Externally publishedYes

Fingerprint

Nucleic acids
nucleic acids
RNA
DNA
deoxyribonucleic acid
Sugars
sugars
Nucleic Acids
Conformations
methylene
linkages
dynamic characteristics
Stabilization
locked nucleic acid
Nucleic Acid Denaturation
Deoxyribose
Sugar Acids
stabilization
Solvation
Structural dynamics

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

Cite this

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title = "Structures, dynamics, and stabilities of fully modified locked nucleic acid (β-D-LNA and α-L-LNA) duplexes in comparison to pure DNA and RNA duplexes",
abstract = "Locked nucleic acid (LNA) is a chemical modification which introduces a-O-CH2-linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state. Two types of modifications, namely, 2′-O,4′-C-methylene-β-d-ribofuranose (β-d-LNA) and 2′-O,4′-C-methylene-α-l-ribofuranose (α-l-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively. LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy. In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties. Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes. Though the α-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures. Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments. π-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution. A combination of two factors, namely, nature of the-O-CH2-linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and α-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties.",
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T1 - Structures, dynamics, and stabilities of fully modified locked nucleic acid (β-D-LNA and α-L-LNA) duplexes in comparison to pure DNA and RNA duplexes

AU - Gorle, Suresh

AU - Priyakumar, U. Deva

PY - 2013/5/9

Y1 - 2013/5/9

N2 - Locked nucleic acid (LNA) is a chemical modification which introduces a-O-CH2-linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state. Two types of modifications, namely, 2′-O,4′-C-methylene-β-d-ribofuranose (β-d-LNA) and 2′-O,4′-C-methylene-α-l-ribofuranose (α-l-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively. LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy. In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties. Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes. Though the α-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures. Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments. π-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution. A combination of two factors, namely, nature of the-O-CH2-linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and α-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties.

AB - Locked nucleic acid (LNA) is a chemical modification which introduces a-O-CH2-linkage in the furanose sugar of nucleic acids and blocks its conformation in a particular state. Two types of modifications, namely, 2′-O,4′-C-methylene-β-d-ribofuranose (β-d-LNA) and 2′-O,4′-C-methylene-α-l-ribofuranose (α-l-LNA), have been shown to yield RNA and DNA duplex-like structures, respectively. LNA modifications lead to increased melting temperatures of DNA and RNA duplexes, and have been suggested as potential therapeutic agents in antisense therapy. In this study, molecular dynamics (MD) simulations were performed on fully modified LNA duplexes and pure DNA and RNA duplexes sharing a similar sequence to investigate their structure, stabilities, and solvation properties. Both LNA duplexes undergo unwinding of the helical structure compared to the pure DNA and RNA duplexes. Though the α-LNA substituent has been proposed to mimic deoxyribose sugar in its conformational properties, the fully modified duplex was found to exhibit unique structural and dynamic properties with respect to the other three nucleic acid structures. Free energy calculations accurately capture the enhanced stabilization of the LNA duplex structures compared to DNA and RNA molecules as observed in experiments. π-stacking interaction between bases from complementary strands is shown to be one of the contributors to enhanced stabilization upon LNA substitution. A combination of two factors, namely, nature of the-O-CH2-linkage in the LNAs vs their absence in the pure duplexes and similar conformations of the sugar rings in DNA and α-LNA vs the other two, is suggested to contribute to the stark differences among the four duplexes studied here in terms of their structural, dynamic, and energetic properties.

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