Geometrical and Electronic Structure Variability of the Sugar−phosphate Backbone in Nucleic Acids

Abstract

The anionic sugar-phosphate backbone of nucleic acids substantially contributes to their structural flexibility. To model nucleic acid structure and dynamics correctly, the potentially sampled substates of the sugar-phosphate backbone must be properly described. However, because of the complexity of the electronic distribution in the nucleic acid backbone, its representation by classical force fields is very challenging. In this work, the three-dimensional potential energy surfaces with two independent variables corresponding to rotations around the R and γ backbone torsions are studied by means of high-level ab initio methods (B3LYP/ 6-31+G*, MP2/6-31+G*, and MP2 complete basis set limit levels). [3817][3818][3819][3820][3821][3822][3823][3824][3825][3826][3827][3828][3829] force fields to describe the various R/γ conformations of the DNA backbone accurately is assessed by comparing the results with those of ab initio quantum chemical calculations. Two model systems differing in structural complexity were used to describe the R/γ energetics. The simpler one, SPM, consisting of a sugar and methyl group linked through a phosphodiester bond was used to determine higher-order correlation effects covered by the CCSD(T) method. The second, more complex model system, SPSOM, includes two deoxyribose residues (without the bases) connected via a phosphodiester bond. It has been shown by means of a natural bond orbital analysis that the SPSOM model provides a more realistic representation of the hyperconjugation network along the C5′-O5′-P-O3′-C3′ linkage. However, we have also shown that quantum mechanical investigations of this model system are nontrivial because of the complexity of the SPSOM conformational space. A comparison of the ab initio data with the ff99 potential energy surface clearly reveals an incorrect ff99 force-field description in the regions where the γ torsion is in the trans conformation. An explanation is proposed for why the R/γ flips are eliminated so successfully when the parmbsc0 force-field modification is used.

The ABCs of molecular dynamics simulations on B-DNA, circa 2012

“…In response, a re-examination of the α/γ torsional behaviour in ff99 was carried out based on refined quantum chemical studies of the relevant part of the DNA backbone, resulting in the modification to ff99 now known as parmbsc0 (Perez et al 2007a, b; Svozil et al 2008). This was a non-trivial undertaking, since not only the behaviour of the α/γ torsional needs to be corrected but extensive testing is required to make sure other errors were not inadvertently introduced.…”

“…Specifically, transitions in the DNA backbone of the γ backbone torsion angle to trans , transitions that should be reversible (Varnai et al 2002), were found to accumulate and eventually degrade the duplex structure. Considerable effort was required to correct this problem properly (Perez et al 2007a, b; Svozil et al 2008) and the whole set of simulations was rerun, this time at the level of 50 ns trajectories. This is referred to as ABC II and is described in an article that appeared in 2010 (Lavery et al 2010).…”

Cisplatin Adducts on a GGG Sequence within a DNA Duplex Studied by NMR Spectroscopy and Molecular Dynamics Simulations

“…[33] An experimental assignment of the g torsion angle using H4'-H5' and H4'-H5'' coupling constants and NOEs was not possible since the H5' and H5'' signals could not be assigned.…”

Convergence and reproducibility in molecular dynamics simulations of the DNA duplex d(GCACGAACGAACGAACGC)

“…During these systematic investigations of the sequence dependence of tetrameric repeats in DNA, we learned about artifacts from anomalous α,γ transitions bringing γ to trans (fixed by parmbsc0) [64] and salt crystal formation at abnormally low concentrations [49,65]. Further improvements to the force fields in Amber removed “ladder-like” structures in RNA helices [66–69] and may improve ε/ζ backbone states in DNA [70]. Similar improvements in the CHARMM force fields for RNA and DNA have been published [71,72].…”