Theoretical studies on the chemical decomposition of 5-aza-2′-deoxycytidine: DFT study and Monte Carlo simulation

Abstract

The decomposition mechanism of 5-Aza-2′-deoxycytidine has been studied by the use of computational techniques. Optimized structures for all of the stationary points in the gas phase were investigated at B3LYP/6-31+G(d,p) level of theory. Single-point energies were determined employing the ab initio MP2 method in conjunction with the 6-311++G(d,p) basis set. Five possible pathways, paths 1–5, were evaluated. In each pathway, the direct (A-paths 1–5) and water-assisted (B-paths 1–5) processes were considered. Meanwhile, the local microhydration model with the direct participation of three water molecules around the reaction centers was adopted to mimic the system for the water-assisted decomposition mechanisms above, where one water molecule is the nucleophilic reactant and the other two are the auxiliary molecules located on each side of the nucleophilic water. The results in the gas phase exhibit that the energy barriers of the water-assisted pathways based on the local microhydration model decrease dramatically by about 15–20 kcal/mol as compared with those of the direct pathways because of the contribution of the auxiliary water molecules. In addition, bulk solvent effects of water were determined by means of the self-consistent reaction field based on the conductor-like polarized continuum model and Monte Carlo simulation with free energy perturbation (MC-FEP) technique, respectively. Our computational results indicate that B-path 3 in the decomposition reaction of 5-azadC is the most favorable, where the calculated rate constant (1.68 × 10−3 min−1) using the MC-FEP method is within the range of the experimentally determined values [(5.89 ± 0.54) × 10−3 min−1 by UV and (1.46 ± 0.08) × 10−3 min−1 by NMR].