Benchmark quantum-chemical calculations on a complete set of rotameric families of the DNA sugar–phosphate backbone and their comparison with modern density functional theory

Abstract

The DNA sugar-phosphate backbone has a substantial influence on the DNA structural dynamics. Structural biology and bioinformatics studies revealed that the DNA backbone in experimental structures samples a wide range of distinct conformational substates, known as rotameric DNA backbone conformational families. Their correct description is essential for methods used to model nucleic acids and is known to be the Achilles heel of force field computations. In this study we report the benchmark database of MP2 calculations extrapolated to the complete basis set of atomic orbitals with aug-cc-pVTZ and aug-cc-pVQZ basis sets, MP2(T,Q), augmented by ΔCCSD(T)/aug-cc-pVDZ corrections. The calculations are performed in the gas phase as well as using a COSMO solvent model. This study includes a complete set of 18 established and biochemically most important families of DNA backbone conformations and several other salient conformations that we identified in experimental structures. We utilize an electronically sufficiently complete DNA sugar-phosphate-sugar (SPS) backbone model system truncated to prevent undesired intramolecular interactions. The calculations are then compared with other QM methods. The BLYP and TPSS functionals supplemented with Grimme's D3(BJ) dispersion term provide the best tradeoff between computational demands and accuracy and can be recommended for preliminary conformational searches as well as calculations on large model systems. Among the tested methods, the best agreement with the benchmark database has been obtained for the double-hybrid DSD-BLYP functional in combination with a quadruple-ζ basis set, which is, however, computationally very demanding. The new hybrid density functionals PW6B95-D3 and MPW1B95-D3 yield outstanding results and even slightly outperform the computationally more demanding PWPB95 double-hybrid functional. B3LYP-D3 is somewhat less accurate compared to the other hybrids. Extrapolated MP2(D,T) calculations are not as accurate as the less demanding DFT-D3 methods. Preliminary force field tests using several charge sets reveal an almost order of magnitude larger deviations from the reference QM data compared to modern DFT-D3, underlining the challenges facing force field simulations of nucleic acids. As expected, inclusion of the solvent environment approximated by a continuum approach has a large impact on the relative stabilities of different backbone substates and is important when comparing the QM data with structural bioinformatics and other experimental data.

Relative Stability of Different DNA Guanine Quadruplex Stem Topologies Derived Using Large-Scale Quantum-Chemical Computations

“…(By rotameric family we mean specific combination of the backbone dihedrals, since backbone of nucleic acids adopts distinct substates due to mutual correlation of the backbone dihedrals). 18,77,102 …”

“…102 TPSS-D3 belongs to the most accurate and efficient methods for evaluation of DNA backbone energies, with accuracy almost an order of magnitude better than achieved by the MM in the same test. 102 …”

Introducing improved structural properties and salt dependence into a coarse-grained model of DNA

“…To do this, we used thermodynamic integration 71 to compute the melting temperatures of duplexes of length 5,6,7,8,10,12, and 15 as a function of q eff at several salt concentrations, and chose the value that best reproduced the melting temperatures predicted by SantaLucia's model.…”

“…10 Theoretical and computational approaches to modelling DNA have been widely exploited to probe the behaviour of the molecule in both a biological and a nanotechnologia) Electronic mail: benedict.snodin@chem.ox.ac.uk b) Electronic mail: jonathan.doye@chem.ox.ac.uk cal context. At the finest level of detail, quantum chemistry calculations have been used to study the interactions between nucleotides, [11][12][13] although the high computational cost of such an approach limits these methods to interactions between nearest-neighbour base pairs in vacuum. Classical all-atom approaches, where every atom of DNA and the surrounding solvent is modelled as a point particle with effective interactions, have been widely employed to study small DNA motifs 14,15 and have recently been applied to larger DNA systems.…”

Multiscale simulation of DNA

“…Their work provided good understanding of the nucleic acids interactions, and benchmarks datasets for force fields validations. Recent examples of this type of works involved detailed analysis of backbone rotamers in DNA [6] and RNA [7] and the impact of ion polarization on the stabilization of certain quadruplexes, which are very difficult to represent by means of classical force-fields [8]. The same groups used also QM to study another complicate DNA motif: the complex of two G-DNA quartets with a monovalent cation.…”