Atomistic investigation of the effect of incremental modification of deoxyribose sugars by locked nucleic acid (β- D -LNA and α- L -LNA) moieties on the structures and thermodynamics of Dna-Rna hybrid duplexes

Suresh Gorle, U. Deva Priyakumar

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10 Citations (Scopus)

Abstract

Chemically modified oligonucleotides offer many possibilities in utilizing their special features for a vast number of applications in nucleic acid based therapies and synthetic molecular biology. Locked nucleic acid analogues (α-/β-LNA) are modifications having an extra ring of 2′-O,4′-C-methylene group in the furanose sugar. LNA strands have been shown to exhibit high binding affinity toward RNA and DNA strands, and the resultant duplexes show significantly high melting temperatures. In the present study, molecular dynamics (MD) simulations were performed on DNA-RNA hybrid duplexes by systematically modifying their deoxyribose sugars with locked nucleic acid analogues. Several geometrical and energetic analyses were performed using principal component (PCA) analysis and binding free energy methods to understand the consequence of incorporated isomeric LNA modifications on the structure, dynamics, and stability of DNA-RNA hybrid duplex. The β-modification systematically changes the conformation of the DNA-RNA hybrid duplex whereas drastic changes are observed for α-modification. The fully modified duplexes have distinct properties compared to partial and unmodified duplexes, and the partly modified duplexes have properties intermediate to full strand and unmodified duplexes. The distribution of BI versus BII populations suggests that backbone rearrangement is minimal for β-LNA modification in order to accommodate it in duplexes whereas extensive backbone rearrangement is necessary in order to incorporate α-LNA modification which subsequently alters the energetic and structural properties of the duplexes. The simulation results also suggest that the alteration of DNA-RNA hybrid properties depends on the position of modification and the gap between the modifications.

Original languageEnglish (US)
Pages (from-to)5853-5863
Number of pages11
JournalJournal of Physical Chemistry B
Volume118
Issue number22
DOIs
StatePublished - Jun 5 2014
Externally publishedYes

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Deoxyribose
Nucleic acids
nucleic acids
sugars
RNA
Thermodynamics
Sugars
DNA
Nucleic Acid Conformation
thermodynamics
deoxyribonucleic acid
Synthetic Biology
strands
RNA Stability
Molecular Dynamics Simulation
Principal Component Analysis
Molecular biology
Oligonucleotides
Nucleic Acids
Freezing

ASJC Scopus subject areas

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

Cite this

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title = "Atomistic investigation of the effect of incremental modification of deoxyribose sugars by locked nucleic acid (β- D -LNA and α- L -LNA) moieties on the structures and thermodynamics of Dna-Rna hybrid duplexes",
abstract = "Chemically modified oligonucleotides offer many possibilities in utilizing their special features for a vast number of applications in nucleic acid based therapies and synthetic molecular biology. Locked nucleic acid analogues (α-/β-LNA) are modifications having an extra ring of 2′-O,4′-C-methylene group in the furanose sugar. LNA strands have been shown to exhibit high binding affinity toward RNA and DNA strands, and the resultant duplexes show significantly high melting temperatures. In the present study, molecular dynamics (MD) simulations were performed on DNA-RNA hybrid duplexes by systematically modifying their deoxyribose sugars with locked nucleic acid analogues. Several geometrical and energetic analyses were performed using principal component (PCA) analysis and binding free energy methods to understand the consequence of incorporated isomeric LNA modifications on the structure, dynamics, and stability of DNA-RNA hybrid duplex. The β-modification systematically changes the conformation of the DNA-RNA hybrid duplex whereas drastic changes are observed for α-modification. The fully modified duplexes have distinct properties compared to partial and unmodified duplexes, and the partly modified duplexes have properties intermediate to full strand and unmodified duplexes. The distribution of BI versus BII populations suggests that backbone rearrangement is minimal for β-LNA modification in order to accommodate it in duplexes whereas extensive backbone rearrangement is necessary in order to incorporate α-LNA modification which subsequently alters the energetic and structural properties of the duplexes. The simulation results also suggest that the alteration of DNA-RNA hybrid properties depends on the position of modification and the gap between the modifications.",
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AU - Priyakumar, U. Deva

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