title: Optimization of an AMBER force field for the artificial nucleic acid, LNA, and benchmarking with NMR of L(CAAU).
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.
authors.affiliation: Department of Chemistry, University of Rochester , Rochester, New York 14627, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Condon
authors.forename: Ilyas
authors.initials: I
authors.lastname: Yildirim
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kennedy
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Mort
authors.forename: Ryszard
authors.initials: R
authors.lastname: Kierzek
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Turner
mesh_terms: D001483:Base Sequence; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D009841:Oligonucleotides; C477371:locked nucleic acid