Reference Simulations of Noncanonical Nucleic Acids with Different χ Variants of the AMBER Force Field: Quadruplex DNA, Quadruplex RNA, and Z-DNA

Abstract

Refinement of empirical force fields for nucleic acids requires their extensive testing using as wide range of systems as possible. However, finding unambiguous reference data is not easy. In this paper, we analyze four systems which we suggest should be included in standard portfolio of molecules to test nucleic acids force fields, namely, parallel and antiparallel stranded DNA guanine quadruplex stems, RNA quadruplex stem, and Z-DNA. We highlight parameters that should be monitored to assess the force field performance. The work is primarily based on 8.4 μs of 100–250 ns trajectories analyzed in detail followed by 9.6 μs of additional selected back up trajectories that were monitored to verify that the results of the initial analyses are correct. Four versions of the Cornell et al. AMBER force field are tested, including an entirely new parmχOL4 variant with χ dihedral specifically reparametrized for DNA molecules containing syn nucleotides. We test also different water models and ion conditions. While improvement for DNA quadruplexes is visible, the force fields still do not fully represent the intricate Z-DNA backbone conformation.

A nucleotide-level coarse-grained model of RNA

“…36,37 Moreover, while the forcefields are improving, they are still under development so that different versions can generate different behavior. [38][39][40] In order to access longer time scales relevant to rare events, such as the breaking of base pairs or the formation of large structures, one needs to use a more coarse-grained description. In this approach, atoms are incorporated into a reduced set of degrees of freedom that experience effective interactions.…”

Computational Methods to Study G-Quadruplex–Ligand Complexes

“…The Czech group led by Jurecka introduced the OL15 force field. 78 They have made similar improvements to the parmbsc0 force field with refinements in the χ 79 , ε/ζ 80 and β torsion angles. 78 A subsequent report by Sponer group to study loop conformations in parallel-stranded quadruplexes highlighted the limitations of these force fields to accurately reproduce experimental structure in all these force field versions.…”

Dynamics of Fluorescent Dyes Attached to G‐Quadruplex DNA and their Effect on FRET Experiments

“…All MD simulations were performed with NAMD [31] version 2.9 with bonds to hydrogen held rigid and at ime step of 2f s. The particlemesh Ewald (PME) algorithm was used for the electrostatics. The AMBER parm99bsc0 force field (FF) parameters with c OL4 corrections [32,33] in CHARMM format [34] were applied to DNA in all simulations. The general AMBER FF parameters [35] were adapted for dyes and linkers.…”