Tautomerism of the natural thymidine nucleoside and the antiviral analogue D4T. Structure and influence of an aqueous environment using MP2 and DFT methods

Abstract

A comparative theoretical conformational analysis of the tautomerism of the four most stable conformers of the antiviral analogue D4T (stavudine) and natural thymidine (Thy) nucleosides was carried out, by using the B3LYP and MP2 quantum chemical methods. The calculated structure data and energy values of the tautomers were compared with the T1 keto form and with the results determined for the thymine molecule. For each conformer, only two stable enol forms, T3 and T5, were obtained when considering different positions of hydrogen around the base. Tautomer T3 always appears more stable than T5, and more stable in the natural nucleoside Thy than in thymine or in D4T.The effect of water on the tautomers was estimated by using an explicit number of up to five water molecules to surround the nucleoside, and also by Tomasi's polarized continuum model (PCM). A total of about 200 clusters were optimised and the geometrical parameters and energies discussed. The water net differs in the three tautomers of D4T and Thy. Depending on the nature of the tautomers, cyclic, distributed water molecules, or clustered structures are formed. The deformation and interaction counterpoise (CP)-corrected energies between the nucleoside and water molecules were determined. The relative stabilities of all tautomers were established. The microhydrated environment stabilizes remarkably the enol forms more than the canonical keto one, although this one continues being the most stable. The changes in the intramolecular H-bondings and in the total atomic charges were discussed. Intramolecular H-bonds being stronger in D4T than in Thy could indicate a higher molecular flexibility for Thy.

Effect of the sulfur atom on S2 and S4 positions of the uracil ring in different DNA:RNA hybrid microhelixes with three nucleotide base pairs

“…From a rigorous theoretical point of view, the latter procedure is the preferred. Moreover, previous studies carried out by us indicated that explicit solvent molecules affect much more on the molecular structure than implicit solvent . Thus, it is the procedure that it is followed in the present work.…”

“…In our simulation, the number of water molecules considered is slightly lower, but the optimized clusters have the main water molecules H‐bonded to the microhelix. In the hydration of our microhelixes with 20 water molecules, several optimized clusters were obtained following the MSM methodology . In each microhelix, the most stable cluster was that with each Na atom surrounded by four water molecules (Figure ).…”

“…The methodology used here for the hydration, the so‐called Modified Scheme of Monosolvation (MSM) from Pullman, was previously used by us in the hydration of several nucleosides . The hydration effects on the microhelixes with U, s 2 U, s 4 U, and s 2,4 U were determined by different numbers of water molecules in explicit form surrounding the nucleobase up to 20.…”

Conformational Analysis, Molecular Structure and Solid State Simulation of the Antiviral Drug Acyclovir (Zovirax) Using Density Functional Theory Methods

“…By the same methodology, the relative energies of the different conformers have been determined in related nucleosides [34,46,47,48]. The global minimum calculated in these molecules by MP2/6-31G(d,p) was in accordance to that found by B3LYP/6-31G(d,p).…”

“…90°). The anti structures are the expected forms in the natural nucleosides that form the nucleotides and polynucleotides in biological systems [33,35,46,47,48]. The ratio anti/syn in conformers A is 0.8 in the low-energy group (<3 kcal/mol) but it increases up to 1.7 in the 3.0–8.5 kcal/mol range.…”