A Kinetic and Thermodynamic Study of the Glycosidic Bond Cleavage in Deoxyuridine

Abstract

Density functional theory was used to study the thermodynamics and kinetics for the glycosidic bond cleavage in deoxyuridine. Two reaction pathways were characterized for the unimolecular decomposition in vacuo. However, these processes are associated with large reaction barriers and highly endothermic reaction energies, which is in agreement with experiments that suggest a (water) nucleophile is required for the nonenzymatic glycosidic bond cleavage. Two (S(N)1 and S(N)2) reaction pathways were characterized for direct hydrolysis of the glycosidic bond by a single water molecule; however, both pathways also involve very large barriers. Activation of the water nucleophile via partial proton abstraction steadily decreases the barrier and leads to a more exothermic reaction energy as the proton affinity of the molecule interacting with water increases. Indeed, our data suggests that the barrier heights and reaction energies range from that for hydrolysis by water to that for hydrolysis by the hydroxyl anion, which represents the extreme of (full) water activation (deprotonation). Hydrogen bonds between small molecules (hydrogen fluoride, water, or ammonia) and the nucleobase were found to further decrease the barrier and overall reaction energy but not to the extent that the same hydrogen-bonding interactions increase the acidity of the nucleobase. Our results suggest that the nature of the nucleophile plays a more important role in reducing the barrier to glycosidic bond cleavage than the nature of the small molecule bound, and models with more than one hydrogen fluoride molecule interacting with the nucleobase provide further support for this conclusion. Our results lead to a greater fundamental understanding of the effects of the nucleophile, activation of the nucleophile, and interactions with the nucleobase for this important biological reaction.

Modeling the Dissociative Hydrolysis of the Natural DNA Nucleosides

“…13,16,27 Other studies that examine both the S N 1 and S N 2 mechanisms report prohibitively large activation energies for the S N 1 dissociation step, and thus conclude that the synchronous mechanism is favored. 25,26,29 In addition, most studies do not contain the empirically proposed oxacarbenium cation intermediate. [24][25][26]29 For example, two studies have reported a reaction intermediate where the nucleobase reattaches to the sugar through a different connectivity compared with the corresponding natural nucleoside, 26,29 such as O2 of thymine glycol bound to C1′ of the sugar moiety.…”

“…25,26,29 In addition, most studies do not contain the empirically proposed oxacarbenium cation intermediate. [24][25][26]29 For example, two studies have reported a reaction intermediate where the nucleobase reattaches to the sugar through a different connectivity compared with the corresponding natural nucleoside, 26,29 such as O2 of thymine glycol bound to C1′ of the sugar moiety. 29 A reaction intermediate whereby the nucleobase (directly or indirectly) abstracts a proton from C2′ of the sugar has also been reported for both nucleoside hydrolysis 25,26,29 and enzymatic depurination.…”

“…40 In all of the uncatalyzed hydrolysis computational studies mentioned above, [25][26][27]29 and many of the enzyme-catalyzed studies, 21,23,24,31,32 environmental effects (if included) were treated as a correction to the energy. Indeed, this is still the most common methodology for studying reaction mechanisms using computational chemistry in the literature, although microsolvation and large-scale models with explicit solvation are increasing in frequency.…”

Extended Lagrangian free energy molecular dynamics

“…27 This is in contrast to regular Born-Oppenheimer-like molecular dynamics, where the initial guess of the SCF optimization is based on some extrapolation of the self-consistent solutions from previous time steps, 2,[28][29][30][31][32] for example,…”

Time-Reversible Born-Oppenheimer Molecular Dynamics

“…Born-Oppenheimer molecular dynamics is computationally expensive compared to Car-Parinello dynamics because of the requirement to reach a self-consistent field (SCF) solution in each timestep. However, the number of SCF cycles and thus the computational cost can be strongly reduced by using an initial guess for the electronic degrees of freedom ρ(t n+1 ) (here represented by the electron density), which is given by an extrapolation from previous time steps [5,8,9,17,18,19]. The electronic extrapolation scheme, combined with the SCF procedure, can be seen as an adiabatic propagation of the electronic degrees of freedom, * Corresponding author: Email amn@lanl.gov where…”