Optimization of an AMBER force field for the artificial nucleic acid, LNA, and benchmarking with NMR of L(CAAU)

J Phys Chem B. 2014 Feb 6;118(5):1216-28. doi: 10.1021/jp408909t. Epub 2014 Jan 24.

Abstract

Locked Nucleic Acids (LNAs) are RNA analogues with an O2'-C4' methylene bridge which locks the sugar into a C3'-endo conformation. This enhances hybridization to DNA and RNA, making LNAs useful in microarrays and potential therapeutics. Here, the LNA, L(CAAU), provides a simplified benchmark for testing the ability of molecular dynamics (MD) to approximate nucleic acid properties. LNA χ torsions and partial charges were parametrized to create AMBER parm99_LNA. The revisions were tested by comparing MD predictions with AMBER parm99 and parm99_LNA against a 200 ms NOESY NMR spectrum of L(CAAU). NMR indicates an A-Form equilibrium ensemble. In 3000 ns simulations starting with an A-form structure, parm99_LNA and parm99 provide 66% and 35% agreement, respectively, with NMR NOE volumes and (3)J-couplings. In simulations of L(CAAU) starting with all χ torsions in a syn conformation, only parm99_LNA is able to repair the structure. This implies methods for parametrizing force fields for nucleic acid mimics can reasonably approximate key interactions and that parm99_LNA will improve reliability of MD studies for systems with LNA. A method for approximating χ population distribution on the basis of base to sugar NOEs is also introduced.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Base Sequence
  • Molecular Dynamics Simulation
  • Nuclear Magnetic Resonance, Biomolecular
  • Nucleic Acid Conformation
  • Oligonucleotides / chemical synthesis
  • Oligonucleotides / chemistry*

Substances

  • Oligonucleotides
  • locked nucleic acid