Developing a computational model that accurately reproduces the structural features of a dinucleoside monophosphate unit within B-DNA

Abstract

The ability of a dinucleoside monophosphate to mimic the conformation of B-DNA was tested using a combination of different phosphate models (anionic, neutral, counterion), environments (gas, water), and density functionals (B3LYP, MPWB1K, M06-2X) with the 6-31G(d,p) basis set. Three sequences (5'-GX(Py)-3', where X(Py) = T, U or (Br)U) were considered, which vary in the (natural or modified) 3' pyrimidine nucleobase (X(Py)). These bases were selected due to their presence in natural DNA, structural similarity to T and/or applications in radical-initiated anti-tumour therapies. The accuracy of each of the 54 model, method and sequence combinations was judged based on the ability to reproduce key structural features of natural B-DNA, including the stacked base-base orientation and important backbone torsion angles. B3LYP yields distorted or tilted relative base-base orientations, while many computational challenges were encountered for MPWB1K. Despite wide use in computational studies of DNA, the neutral (protonated) phosphate model could not consistently predict a stacked arrangement for all sequences. In contrast, stacked base-base arrangements were obtained for all sequences with M06-2X in conjunction with both the anionic and (sodium) counterion phosphate models. However, comparison of calculated and experimental backbone conformations reveals the charge-neutralized counterion phosphate model best mimics B-DNA. Structures optimized with implicit solvent (water) are comparable to gas-phase structures, which suggests similar results should be obtained in an environment of intermediate polarity. We recommend the use of either gas-phase or water M06-2X optimizations with the counterion phosphate model to study the structure and/or reactivity of natural or modified DNA with a dinucleoside monophosphate.

A Thiazole Coumarin (TC) Turn-On Fluorescence Probe for AT-Base Pair Detection and Multipurpose Applications in Different Biological Systems

“…We used 6-31g(d) basis set for all the atoms (see supplementary information). The DNA phosphate backbone was neutralized by protonating one of the oxygen atoms of the phosphate groups, which does not alter any property of the DNA duplex structure434445. The DFT and TD-DFT calculations were performed with surrounding water, using a Polarized Continuum Model (PCM) to include the solvent (water) effect.…”

B‐DNA Structure and Stability as Function of Nucleic Acid Composition: Dispersion‐Corrected DFT Study of Dinucleoside Monophosphate Single and Double Strands

“…This issue has been recently considered in the choice of model systems in density functional theory (DFT) calculations of the structure of dinucleoside monophosphate single strands. [3] The results obtained show that, not unexpectedly, the presence of the Na + counterions at each phosphate group is even more important than the presence of the implicit solvent for providing a structure in which the relative base–base orientation and the backbone torsion angles are in better agreement with experimental B-DNA crystal structures. This result reconfirms the importance of charge neutralization in DNA model systems.…”

“…Model systems in pioneering DFT studies so far cover single-stranded GC dinucleoside monophosphate models (including sodium counter ions and implicit water solvent),[3] the ten possible combinations of DNA bases A, T, G and C in stacks of two Watson–Crick pairs (but without sugar-phosphate bridge between the Watson–Crick pairs),[7] and double-stranded DNA dimers (but with the sugar-phosphate bridge in the MM part of a QM/MM approach). [8]…”

Structural and Magnetic Properties of a Variety of Transition Metal Incorporated DNA Double Helices

“…The DNA phosphate backbone was neutralized by protonating one of the oxygen of the phosphate groups, which does not alter the stability of the DNA duplex structure. [16,17] The DFT calculations were carried out in super-cells chosen such that the interactions between the neighboring fragments were negligible. [18] We denote hydroxypyrido-incorporated DNA and bis(salicyclaldehyde)ethylenediamine-incorporated DNA as nH-DNA and nS-en-DNA, respectively, in which n corresponds to the number of MBP aligned within the DNA helix.…”