Substituting CF₂for O4′ in Components of Nucleic Acids: Towards Systems with Reduced Propensity to Form Abasic Lesions

Abstract

Intrinsic structural features and energetics of nucleotides containing variously fluorinated sugars as potential building blocks of DNA duplexes and quadruplexes are explored systematically using the modern methods of density functional theory (DFT) and quantum chemical topology (QCT). Our results suggest that fluorination at the 2'-β or 2'-α,β positions somewhat stabilizes in vacuo the AI relative to the BI conformations. In contrast, substitution of the CF2 group for the O4' atom (O4'-CF2 modification) leads to a preference of the BI relative to AI DNA-like conformers. All the studied modifications result in a noticeable increase in the stability of the glycosidic bond [estimated by the relaxed force constants (RFC) approach], with particularly encouraging results for the O4'-CF2 derivative. Consequently, the O4'-CF2 modified systems are suggested and explored as promising scaffolds for the development of duplex and quadruplex structures with reduced propensity to form abasic lesions and to undergo DNA damage.

The Weakness of B−H⋅⋅⋅π Interactions: Much Softer than a Hydrogen Bond

“…Nevertheless, the use of force constants as bond strength descriptors as such is a non‐trivial task by its own. Since our original proposal, more and more reports have appeared that benefit from the use of force constants as bond strength descriptors for non‐covalent interactions . In any case, there still seem to be some misunderstandings in the literature that need clarification.…”

Weak Supramolecular Interactions Governing Parallel and Antiparallel DNA Quadruplexes: Insights from Large‐Scale Quantum Mechanics Analysis of Experimentally Derived Models

“…In contrast to previous MD simulations, DFT‐D3 computations clearly indicate that the parallel ( P ) structure with the AA stem orientation is more stable than the antiparallel ( AP ) GQ with the SA stem, which is in line with the fact that quadruplexes experimentally tend to form all‐parallel stems with all‐ anti orientation of nucleobases . Subsequently, the two‐stack dinucleotide model was employed in other QM investigations of GQs, for example, to explain the preferential binding of K + to quadruplex stems over Na +[47] or to analyze the impact of base and sugar residue modifications on the energetics and chemical stability of GQs . However, the abovementioned studies on dinucleotide models did not consider explicit solvation, which currently cannot be adequately treated with modern QM approaches.…”

“…The situation has changed with the advance of modern DFT methods, which, in combination with a posteriori dispersion corrections, have been applied to large‐scale GQ fragments (consisting of hundreds atoms) and proved to provide valuable insights into structures and energetics of quadruplex stems. The pioneering DFT‐D3 study by Šponer and co‐workers, who employed two‐stack (two parallel G‐tetrads) dinucleotide models, was published in 2013 and predicted the relative stability of seven GQ stem topologies .…”

“…The situation has changed with the advance of modernD FT methods, which, in combinationw ith ap osteriori dispersion corrections, [44] have been applied [20,[45][46][47][48] to large-scale GQ fragments (consisting of hundreds atoms) andp roved to provide valuablei nsights into structures and energetics of quadruplex stems.T he pioneering DFT-D3 study by Šponer and co-workers, who employedt wo-stack (two parallelG -tetrads) dinucleotide models, was published in 2013 andp redicted the relative stabilityo fs even GQ stem topologies. [20] In contrastt op revious MD simulations, [19] DFT-D3 computations clearlyi ndicate that the parallel( P)s tructure with the AA stem orientation is more stable than the antiparallel (AP)G Qw ith the SA stem, [20] which is in line with the fact that quadruplexese xperimentally tend to form all-parallel stemsw ith all-anti orientation of nucleobases.…”

Modified Guanines as Constituents of Smart Ligands for Nucleic Acid Quadruplexes

“…The presence of the G‐quadruplex in the telomeric sequence blocks the interaction of telomerase with the DNA strand and protects it from excessive elongation . Therefore, many studies are devoted to understanding the properties of quadruplexes, how they are formed, and how we can manipulate their stability to effectively influence cancer processes …”