Refinement of the Cornell et al. Nucleic Acids Force Field Based on Reference Quantum Chemical Calculations of Glycosidic Torsion Profiles

Abstract

We report a reparameterization of the glycosidic torsion χ of the Cornell et al. AMBER force field for RNA, χOL. The parameters remove destabilization of the anti region found in the ff99 force field and thus prevent formation of spurious ladder-like structural distortions in RNA simulations. They also improve the description of the syn region and the syn–anti balance as well as enhance MD simulations of various RNA structures. Although χOL can be combined with both ff99 and ff99bsc0, we recommend the latter. We do not recommend using χOL for B-DNA because it does not improve upon ff99bsc0 for canonical structures. However, it might be useful in simulations of DNA molecules containing syn nucleotides. Our parametrization is based on high-level QM calculations and differs from conventional parametrization approaches in that it incorporates some previously neglected solvation-related effects (which appear to be essential for obtaining correct anti/high-anti balance). Our χOL force field is compared with several previous glycosidic torsion parametrizations.

Small Details Matter: The 2′-Hydroxyl as a Conformational Switch in RNA

“…Interestingly, no significant differences are found in the  torsional distribution for the four ribonucleotides ( Supplementary Figure 2), suggesting that base-sugar contacts are not crucial to determine the 2'OH group orientation (see below). Contact analysis reveals some interactions that appear in all the conformations of this set of structures, such as a non-canonical C5' (n+1) -H5' (n+1) ···O2' hydrogen bond and the non-canonical C2'-H2'···O4' (n+1) hydrogen bond previously reported by Auffinger and Westhof, 8 while others like the strong O2'-HO2'···O3' hydrogen bond, appear only in conformer 1 ( Figure 1F-I). Close contacts between the 2'OH group and the nucleobase, or the OP1/2 groups are uncommon in experimental structures of north riboses (Supplementary Figure 3).…”

“…8 The first two are the most frequent ones, according to NMR 9 and quantum mechanics (QM) calculations, 10 and subject to orientation-specific hydration. When water interacts with the 2'OH in the base orientation the A-form is stabilized, 9,11 while non-canonical conformations gain stabilization from water molecules interacting with the 2'OH in the O3' orientation.…”

“…12 The less frequent south sugar conformation has received less attention but is believed to favor a 2'OH oriented mainly toward the O3' atom but with a C2'-O2' torsion shifted to trans orientation. 8,10 In the present work, a combination of database analysis, atomistic molecular dynamics (MD), high-level QM and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations was used to explore in detail the conformational preferences of the C2'OH bond and its specific impact on the sugar puckering, which in turn, defines the RNA conformation.…”

CRISPR-Cas9 conformational activation as elucidated from enhanced molecular simulations

“…Conventional MD simulations were performed using a well-established protocol used for several other endonucleases (31), using the Amber ff12SB force field, which includes the ff99bsc0 corrections for DNA (32) and the ff99bsc0+χOL3 corrections for RNA (33,34). The Åqvist (35) force field has been used for Mg ions.…”

Using Molecular Modelling to Study Interactions Between Molecules with Biological Activity

“…The results obtained with this method can be very good for proteins and nucleic acids, but less so for other systems, although parameters that enable the simulation of other systems have been published [for examples see Doshi & Hamelberg, 2009;Zgarbová et al, 2011] [Brooks et al, 1983], and is now used for a range of macromolecules, molecular dynamics, solvation, crystal packing, vibrational analysis and QM/MM (quantum mechanics/molecular mechanics) studies. It uses five valence terms, one of which is electrostatic and is a basis for other force fields (e.g., MOIL [Elber et al, 1995]).…”